Method for producing sulfone derivatives

Abstract

The present invention provides an industrially desirable production method for a sulfone derivative that is useful as a herbicide, and an intermediate thereof.

Description

[Technical Field]

[0001] The present invention relates to a method for producing a sulfone derivative useful as a herbicide, namely a compound of the following formula (8).

[0002] [ka]

[0003] (In the formula, R 1 , R 2 , R 3 , R 4 and R 5 (As described herein.) [Background technology]

[0004] The sulfone derivatives of formula (8) above are known to have herbicidal activity, as disclosed in WO2002 / 062770A1 (Patent Document 1). Among them, the compound of formula (8-a) (pyroxasulfone) is well known as an excellent herbicide. TIFF0007846022000002.tif5964

[0005] A known method for producing the compound of formula (8) involves the oxidation of a sulfide derivative, i.e., the compound of formula (7), and this method is described below.

[0006] [ka]

[0007] As shown in the figure below, in Reference Example 3 of WO2004 / 013106A1 (Patent Document 2), 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline (7-a) (ISFP) is oxidized with m-chloroperbenzoic acid (mCPBA) to produce 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethanesulfonyl)-5,5-dimethyl-2-isoxazoline (8-a) (Pyroxasulfone).

[0008] [Chemical formula]

[0009] In the method for producing the compound of formula (8) from the compound of formula (7), m-chloroperbenzoic acid (mCPBA) described in WO2004 / 013106A1 (Patent Document 2) is expensive for industrial use and has problems in handling and waste. Therefore, the production method described in WO2004 / 013106A1 (Patent Document 2) is not practical for production on an industrial scale.

[0010] Also, in the method for producing the compound of formula (8) (sulfone derivative: SO2 derivative) from the compound of formula (7) (sulfide derivative: S derivative), the sulfoxide derivative (SO derivative), which is an intermediate of the oxidation reaction, that is, the following formula (9):

[0011] [Chemical formula]

[0012] (where R 1 , R 2 , R 3 , R 4 and R 5 are as described in this specification.) The reaction may be stopped by the compound (9). Therefore, the compound of formula (9) may remain in the product as a byproduct. If the compound of formula (9) is mixed into products such as herbicides, it may lead to a decrease in quality and phytotoxicity to crops. However, since the physical and chemical properties of the compound of formula (9) are very similar to those of the compound of formula (8), it is difficult to separate the compound of formula (9) and purify the compound of formula (8). Therefore, in a method for producing the compound of formula (8) from the compound of formula (7), a method is needed in which the oxidation reaction proceeds sufficiently and the amount of the compound of formula (9) in the product is sufficiently small.

[0013] WO2021 / 002484A9 (Patent Document 9) describes a method for producing pyroxasulfone. This method is an excellent method that solves the above-mentioned problems. However, because it uses transition metals, there is still room for improvement in this method.

[0014] CN111574511A (Patent Document 10), Example 4, describes a manufacturing method that does not use transition metals. However, the described yield is low and not reproducible. [Prior art documents] [Patent Documents]

[0015] [Patent Document 1] International Publication No. 2002 / 062770 [Patent Document 2] International Publication No. 2004 / 013106 [Patent Document 3] International Publication No. 2005 / 095352 [Patent Document 4] International Publication No. 2005 / 105755 [Patent Document 5] International Publication No. 2007 / 094225 [Patent Document 6] International Publication No. 2006 / 068092 [Patent Document 7] Special Publication No. 2013-512201 [Patent Document 8] International Publication No. 2019 / 131715 [Patent Document 9] International Publication No. 2021 / 002484 [Patent Document 10] Chinese Patent Publication No. 111574511 [Overview of the Initiative] [Problems that the invention aims to solve]

[0016] The object of the present invention is to provide an industrially preferred method for producing a compound of formula (8) from a compound of formula (7), wherein the proportion of compound of formula (9) in the product is sufficiently low, yields excellent results, and is advantageous for industrial-scale production.

[0017] Another object of the present invention is to provide an environmentally friendly method for producing the compound of formula (8). [Means for solving the problem]

[0018] As a result of diligent research, the inventors have discovered that, as shown in step ii below, the compound of formula (8) can be efficiently produced by reacting the compound of formula (7) with an oxidizing agent using an oxidation method that does not use a transition metal as a catalyst. Based on this finding, the inventors have completed the present invention.

[0019] [ka]

[0020] (In the formula, R 1 , R 2 , R 3 , R 4 and R 5 (As described herein.)

[0021] Furthermore, the inventors have discovered that in a method for producing the compound of formula (8) from the compound of formula (7), the oxidation reaction can be sufficiently carried out by reacting with an oxidizing agent (preferably hydrogen peroxide, or an alkali metal persulfate, ammonium persulfate, or alkali metal bisulfate, more preferably hydrogen peroxide) under specific conditions. Based on this finding, the inventors have completed a production method in which the amount of the compound of formula (9) in the product is sufficiently small. [Effects of the Invention]

[0022] The present invention provides a novel method for producing the compound of formula (8), which offers excellent yield and is environmentally friendly because it does not use transition metals. Therefore, the present invention contributes to sustainability.

[0023] Furthermore, the present invention provides a method for producing a compound of formula (8) (sulfone derivative: SO2 derivative) from a compound of formula (7) (sulfide derivative: S derivative), wherein the proportion of compound of formula (9) (sulfoxide derivative: SO derivative) in the product is sufficiently low, the yield is excellent, and the production method is advantageous for industrial-scale production. The amount of compound of formula (9) in the compound of formula (8) produced by the present invention is sufficiently low, which may cause a decrease in quality as a herbicide and phytotoxicity to crops, making it useful as a herbicide.

[0024] The method of the present invention can be implemented on a large scale using inexpensive raw materials, is highly economically efficient, and is suitable for industrial-scale production. [Modes for carrying out the invention]

[0025] In one embodiment, the present invention is as follows:

[0026] [I-1] A method for producing the compound of formula (8), comprising the following step ii: (Step ii) In the absence of a transition metal, the compound of formula (7) is reacted with an oxidizing agent to produce the compound of formula (8);

[0027] [ka]

[0028] (In the formula, R 1 , R 2 and R 3 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents. R 4 and R 5 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; a (C1-C6) alkoxy which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents; or R 4 and R 5 These atoms, together with the carbon atoms to which they are bonded, form a 4- to 12-membered carbon ring, which may be substituted with one or more substituents.

[0029] [I-2] A method for producing the compound of formula (8), comprising the following steps ia and ii: (Step ia) In the presence of a base, the compound of formula (1) is reacted with the compound of formula (2) to produce the compound of formula (7);

[0030] [ka]

[0031] (In equations (1), (2), and (7), R 1 , R 2 , R 3 , R 4 and R 5 As defined above, X 1 X is a leaving group, 2 (A is an atom or group of atoms that forms an acid.)

[0032] (Step ii) In the absence of a transition metal, the compound of formula (7) is reacted with an oxidizing agent to produce the compound of formula (8);

[0033] [ka]

[0034] (In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5 This is as defined above.

[0035] [I-3] A method for producing the compound of formula (8), comprising the following steps ib and ii: (Step ib) In the presence of a base, the compound of formula (4) is reacted with the compound of formula (3) to produce the compound of formula (7);

[0036] [ka]

[0037] (In equations (3), (4), and (7), R 1 , R 2 , R 3 , R 4 and R 5 As defined above, X 4 (This is a leaving group.)

[0038] (Step ii) In the absence of a transition metal, the compound of formula (7) is reacted with an oxidizing agent to produce the compound of formula (8);

[0039] [ka]

[0040] (In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5 This is as defined above.

[0041] [I-4] A method for producing the compound of formula (8), comprising the following steps ic and ii: (Step ic) In the presence of a base, the compound of formula (5) is reacted with the compound of formula (6) to produce the compound of formula (7);

[0042] [ka]

[0043] (In equations (5), (6), and (7), R 1 , R 2 , R 3 , R 4 and R 5 As defined above, X 3 X is a leaving group, 5 (A is an atom or group of atoms that forms an acid.)

[0044] (Step ii) In the absence of a transition metal, the compound of formula (7) is reacted with an oxidizing agent to produce the compound of formula (8);

[0045] [ka]

[0046] (In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5This is as defined above.

[0047] [I-5] A method according to any one of [I-1] to [I-4], wherein the reaction in step ii is carried out in the presence of an acidic compound.

[0048] [I-6] A method according to [I-5], wherein the acidic compound in step ii is selected from mineral acids and carboxylic acids.

[0049] [I-7] The method according to [I-5], wherein the acidic compound in step ii is selected from sulfuric acid, acetic acid, and trifluoroacetic acid.

[0050] A method according to [I-8] and [I-5], wherein the acidic compound in step ii is selected from sulfuric acid, sodium bisulfate, potassium bisulfate, acetic acid, and trifluoroacetic acid.

[0051] A method according to [I-9] and [I-5], wherein the acidic compound in step ii is selected from sulfuric acid, potassium bisulfate, acetic acid, and trifluoroacetic acid.

[0052] A method according to [I-10] and [I-5], wherein the acidic compound in step ii is sulfuric acid.

[0053] A method according to [I-11] and [I-5], wherein the acidic compound in step ii is a (C1-C4) alkanoic acid.

[0054] A method according to [I-12] and [I-5], wherein the acidic compound in step ii is acetic acid.

[0055] A method according to [I-13] and [I-5], wherein the acidic compound in step ii is a (C2-C4) alkanoic acid substituted with 1 to 7 fluorine atoms.

[0056] A method according to [I-14] and [I-5], wherein the acidic compound in step ii is trifluoroacetic acid.

[0057] [I-15] A method according to any one of [I-5] to [I-14], wherein the amount of the acidic compound used in step ii is greater than 0.10 moles per mole of the compound of formula (7).

[0058] [I-16] A method according to any one of [I-5] to [I-14], wherein the amount of the acidic compound used in step ii is 0.5 moles or more per mole of the compound of formula (7).

[0059] [I-17] A method according to any one of [I-5] to [I-14], wherein the amount of the acidic compound used in step ii is 1 mole or more per mole of the compound of formula (7).

[0060] [I-18] A method according to any one of [I-5] to [I-14], wherein the amount of the acidic compound used in step ii is 2 moles or more per 1 mole of the compound of formula (7).

[0061] [I-19] A method according to any one of [I-5] to [I-14], wherein the amount of the acidic compound used in step ii is 100 moles or less per mole of the compound of formula (7).

[0062] [I-20] A method according to any one of [I-5] to [I-14], wherein the amount of the acidic compound used in step ii is 50 moles or less per mole of the compound of formula (7).

[0063] [I-21] A method according to any one of [I-5] to [I-14], wherein the amount of the acidic compound used in step ii is 30 moles or less per mole of the compound of formula (7).

[0064] [I-22] A method according to any one of [I-1] to [I-21], wherein the reaction in step ii is carried out in the presence of an organic solvent.

[0065] [I-23] A method according to [I-22], wherein the organic solvent for the reaction in step ii is selected from aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, alcohols, carboxylic acids, nitriles, carboxylic acid esters, ethers, ketones, amides, ureas, and sulfones.

[0066] [I-24] A method according to [I-22], wherein the organic solvent in the reaction of step ii is one or more (preferably one or two, more preferably one) organic solvents selected from aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, alcohols, carboxylic acids, nitriles, carboxylic acid esters, ethers, ketones, amides, ureas, and sulfones.

[0067] [I-25] A method according to [I-22], wherein the organic solvent for the reaction in step ii is selected from aromatic hydrocarbon derivatives, carboxylic acids, alcohols, and nitriles.

[0068] [I-26] A method according to [I-22], wherein the organic solvent in the reaction of step ii is one or more (preferably one or two, more preferably one) organic solvents selected from aromatic hydrocarbon derivatives, carboxylic acids, alcohols, and nitriles.

[0069] [I-27] A method according to [I-22], wherein the organic solvent for the reaction in step ii is selected from carboxylic acids, alcohols, and nitriles.

[0070] [I-28] A method according to [I-22], wherein the organic solvent in step ii of the reaction is one or two (preferably one) organic solvents selected from carboxylic acids, alcohols, and nitriles.

[0071] [I-29] The method according to [I-22], wherein the organic solvent in step ii of the reaction is one or more organic solvents selected from acetic acid, methanol, and acetonitrile.

[0072] [I-30] The method according to [I-22], wherein the organic solvent in step ii of the reaction is one or two (preferably one) organic solvents selected from acetic acid, methanol, and acetonitrile.

[0073] [I-31] A method according to [I-22], wherein the organic solvent in the reaction of step ii is an organic solvent having a dielectric constant of 1 to 40.

[0074] [I-32] A method according to [I-22], wherein the organic solvent in step ii of the reaction is an organic solvent having a Rohrschneider polarity parameter of 1 to 7.

[0075] [I-33] A method according to [I-22], wherein the organic solvent in step ii of the reaction is an organic solvent having 5 to 25 acceptors.

[0076] [I-34] The method according to [I-22], wherein the organic solvent in step ii of the reaction is an organic solvent other than alcohols.

[0077] [I-35] A method according to [I-22], wherein the organic solvent in step ii of the reaction is an organic solvent other than (C1-C6) alcohols.

[0078] [I-36] A method according to [I-22], wherein the organic solvent in step ii of the reaction is an organic solvent other than (C1-C4) alcohols.

[0079] [I-37] A method according to [I-22], wherein the organic solvent for the reaction in step ii is selected from aromatic hydrocarbon derivatives, nitriles, carboxylic acid esters, and amides.

[0080] [I-38] A method according to [I-22], wherein the organic solvent in the reaction of step ii is one or more (preferably one or two, more preferably one) organic solvents selected from aromatic hydrocarbon derivatives, nitriles, carboxylic acid esters, and amides.

[0081] [I-39] A method according to [I-22], wherein the organic solvent for the reaction in step ii is selected from aromatic hydrocarbon derivatives, nitriles, and carboxylic acid esters.

[0082] [I-40] A method according to [I-22], wherein the organic solvent in step ii of the reaction is one or more (preferably one or two, more preferably one) organic solvents selected from aromatic hydrocarbon derivatives, nitriles, and carboxylic acid esters.

[0083] [I-41] A method according to [I-22], wherein the organic solvent for the reaction in step ii is selected from benzene, (C2-C5)alkanenitrile, (C1-C4)alkyl(C1-C6)carboxylate, N,N-di((C1-C4)alkyl)(C1-C4)alkaneamide and 1-(C1-C4)alkyl-2-pyrrolidone, wherein the organic solvent for the reaction in step ii may be substituted with 1 to 3 (preferably 1 or 2, more preferably 1) selected from (C1-C4)alkyl groups and chlorine atoms.

[0084] [I-42] A method according to [I-22], wherein the organic solvent in the reaction of step ii is one or more organic solvents selected from benzene, (C2-C5) alkanenitrile, (C1-C4) alkyl(C1-C6) carboxylate, N,N-di((C1-C4)alkyl)(C1-C4) alkaneamide and 1-(C1-C4) alkyl-2-pyrrolidone, which may be substituted with 1 to 3 (preferably 1 or 2, more preferably 1) selected from (C1-C4) alkyl groups and chlorine atoms.

[0085] [I-43] A method according to [I-22], wherein the organic solvent for the reaction in step ii is selected from benzene, (C2-C5) alkanenitrile, and (C1-C4) alkyl(C1-C6) carboxylate, which may be substituted with 1 to 3 (preferably 1 or 2, more preferably 1) selected from (C1-C4) alkyl groups and chlorine atoms.

[0086] [I-44] A method according to [I-22], wherein the organic solvent in step ii is one or more organic solvents selected from benzene, (C2-C5) alkanenitrile, and (C1-C4) alkyl(C1-C6) carboxylate, which may be substituted with 1 to 3 (preferably 1 or 2, more preferably 1) selected from (C1-C4) alkyl groups and chlorine atoms.

[0087] [I-45] The method according to [I-22], wherein the organic solvent for the reaction in step ii is selected from toluene, xylene, chlorobenzene, dichloronzene, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, hexyl acetate and its isomers, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, and N-methylpyrrolidone (NMP).

[0088] [I-46] The method according to [I-22], wherein the organic solvent in step ii of the reaction is acetonitrile.

[0089] [I-47] A method according to any one of [I-6] to [I-14], wherein the amount of the acidic compound used in step ii is 0.1 moles to 10.0 moles per mole of the compound of formula (7).

[0090] [I-48] A method according to any one of [I-6] to [I-14], wherein the amount of the acidic compound used in step ii is 0.2 moles to 5.0 moles per mole of the compound of formula (7).

[0091] [I-49] A method according to any one of [I-6] to [I-14], wherein the amount of the acidic compound used in step ii is 0.3 moles to 3.0 moles per mole of the compound of formula (7).

[0092] [I-50] A method according to any one of [I-6] to [I-14], wherein the amount of the acidic compound (preferably sulfuric acid) used in step ii is 0.1 moles to 3.0 moles per mole of the compound of formula (7).

[0093] [I-51] A method according to any one of [I-6] to [I-14], wherein the amount of the acidic compound (preferably sulfuric acid) used in step ii is 0.3 moles to 2.0 moles per mole of the compound of formula (7).

[0094] [I-52] A method according to any one of [I-6] to [I-14], wherein the amount of the acidic compound (preferably sulfuric acid) used in step ii is 0.5 moles to 1.0 mole per mole of the compound of formula (7).

[0095] [I-53] A method according to any one of [I-6] to [I-14], wherein the amount of the acidic compound (preferably trifluoroacetic acid) used in step ii is 0.1 moles to 3.0 moles per mole of the compound of formula (7).

[0096] [I-54] A method according to any one of [I-6] to [I-14], wherein the amount of the acidic compound (preferably trifluoroacetic acid) used in step ii is 0.3 moles to 2.0 moles per mole of the compound of formula (7).

[0097] [I-55] A method according to any one of [I-6] to [I-14], wherein the amount of the acidic compound (preferably trifluoroacetic acid) used in step ii is 0.5 moles to 1.0 mole per mole of the compound of formula (7).

[0098] [I-56] A method according to any one of [I-1] to [I-55], wherein the reaction in step ii is carried out at 30°C to 100°C.

[0099] [I-57] A method according to any one of [I-1] to [I-55], wherein the reaction in step ii is carried out at 30°C to 80°C.

[0100] [I-58] A method according to any one of [I-1] to [I-55], wherein the reaction in step ii is carried out at 40°C to 80°C.

[0101] [I-59] A method according to any one of [I-22] to [I-46], wherein the amount of organic solvent used in the reaction of step ii is 0.3 to 3 liters (preferably 0.3 to 2 liters) per mole of the compound of formula (7).

[0102] [I-60] A method according to any one of [I-22] to [I-46], wherein the amount of organic solvent used in the reaction of step ii is 0.4 to 1.8 liters per mole of the compound of formula (7).

[0103] [I-61] A method according to any one of [I-1] to [I-60], wherein the reaction in step ii is carried out over a period of 1 to 48 hours.

[0104] [I-62] A method according to any one of items [I-1] to [I-60], wherein the reaction in step ii is carried out over 1 to 24 hours.

[0105] [I-63] A method according to [I-22], wherein the organic solvent in step ii is a carboxylic acid.

[0106] [I-64] The method according to [I-22], wherein the organic solvent in step ii of the reaction is (C1-C4) alkanoic acid.

[0107] [I-65] The method according to [I-22], wherein the organic solvent in step ii of the reaction is acetic acid.

[0108] [I-66] A method according to any one of [I-5] to [I-65], wherein the acidic compound in step ii is selected from sulfuric acid and trifluoroacetic acid.

[0109] [I-67] A method according to any one of [I-5] to [I-65], wherein the amount of the acidic compound (preferably sulfuric acid or trifluoroacetic acid) used in step ii is 0 to 10.0 moles per mole of the compound of formula (7).

[0110] [I-68] A method according to any one of [I-5] to [I-65], wherein the amount of the acidic compound (preferably sulfuric acid or trifluoroacetic acid) used in step ii is 0 to 5.0 moles per mole of the compound of formula (7).

[0111] [I-69] A method according to any one of [I-5] to [I-65], wherein the amount of the acidic compound (preferably sulfuric acid or trifluoroacetic acid) used in step ii is 0 to 3.0 moles per mole of the compound of formula (7).

[0112] [I-70] A method according to any one of [I-1] to [I-69], wherein the reaction in step ii is carried out at 10°C to 100°C.

[0113] [I-71] A method according to any one of [I-1] to [I-69], wherein the reaction in step ii is carried out at 15°C to 90°C.

[0114] [I-72] A method according to any one of [I-1] to [I-69], wherein the reaction in step ii is carried out at 20°C to 80°C.

[0115] [I-73] A method according to any one of [I-22] to [I-46] and [I-63] to [I-65], wherein the amount of organic solvent used in the reaction of step ii is 0.3 to 3 liters (preferably 0.3 to 2 liters) per mole of the compound of formula (7).

[0116] [I-74] A method according to any one of [I-22] to [I-46] and [I-63] to [I-65], wherein the amount of organic solvent used in the reaction of step ii is 0.4 to 1.8 liters per mole of the compound of formula (7).

[0117] [I-75] A method according to any one of [I-1] to [I-74], wherein the reaction in step ii is carried out in the presence of an aqueous solvent.

[0118] [I-76] A method according to [I-75], wherein the amount of aqueous solvent used in the reaction of step ii is 0.05 to 1.0 liters (preferably 0.1 to 0.5 liters) per mole of the compound of formula (7).

[0119] [I-77] A method according to [I-75] or [I-76], wherein the amount of aqueous solvent in the total solvent, which consists of an organic solvent and an aqueous solvent, is 5 to 50 vol% (preferably 5 to 40 vol%) of the total amount of solvent.

[0120] [I-78] A method according to any one of items [I-1] to [I-77], wherein the reaction in step ii is carried out over a period of 1 to 48 hours.

[0121] [I-79] A method according to any one of items [I-1] to [I-77], wherein the reaction in step ii is carried out over 1 to 24 hours.

[0122] [I-80] A method according to any one of [I-1] to [I-4], wherein the reaction in step ii is carried out in the presence of a base.

[0123] [I-81] A method according to [I-80], wherein the base in step ii is selected from metal bicarbonates and metal carbonates.

[0124] [I-82] A method according to [I-80], wherein the base in step ii is selected from alkali metal carbonates, alkali metal carbonates, alkaline earth metal bicarbonates, and alkaline earth metal carbonates.

[0125] [I-83] A method according to [I-80], wherein the base in step ii is selected from alkali metal bicarbonates and alkali metal carbonates.

[0126] [I-84] The method according to [I-80], wherein the base in step ii is an alkali metal carbonate, an alkali metal bicarbonate, or a mixture thereof.

[0127] [I-85] A method according to [I-80], wherein the base in step ii is selected from lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, and calcium carbonate.

[0128] [I-86] The method according to [I-80], wherein the base in step ii is lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, or a mixture thereof.

[0129] [I-87] A method according to [I-80], wherein the base in step ii is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

[0130] [I-88] A method according to [I-80], wherein the base in step ii is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, or a mixture thereof.

[0131] [I-89] A method according to [I-80], wherein the base in step ii is selected from sodium carbonate and potassium carbonate.

[0132] [I-90] A method according to [I-80], wherein the base in step ii is sodium carbonate or potassium carbonate.

[0133] [I-91] The method according to [I-80], wherein the base in step ii is sodium carbonate.

[0134] [I-92] The method according to [I-80], wherein the base in step ii is potassium carbonate.

[0135] [I-93] A method according to any one of [I-80] to [I-92], wherein the amount of base used in step ii is 0.01 to 1 mole per mole of the compound of formula (7).

[0136] [I-94] A method according to any one of [I-80] to [I-92], wherein the amount of base used in step ii is 0.05 to 1 mole per mole of the compound of formula (7).

[0137] [I-95] A method according to any one of [I-80] to [I-92], wherein the amount of base used in step ii is 0.1 to 0.8 moles per mole of the compound of formula (7).

[0138] [I-96] A method according to any one of [I-80] to [I-92], wherein the amount of base used in step ii is 0.05 to 5 moles (preferably 0.1 to 3 moles) per mole of the compound of formula (7).

[0139] [I-97] A method according to any one of [I-80] to [I-92], wherein the amount of base used in step ii is 0.4 to 1.5 per mole of the compound of formula (7).

[0140] [I-98] A method according to any one of [I-80] to [I-92], wherein the amount of base used in step ii is 0.2 to 2 moles per mole of the compound of formula (7).

[0141] [I-99] A method according to any one of [I-80] to [I-92], comprising the simultaneous addition of the base of step ii and the oxidizing agent of step ii.

[0142] [I-100] A method according to any one of [I-80] to [I-92], wherein the base of step ii and the oxidizing agent of step ii are added simultaneously.

[0143] [I-101] A method according to any one of [I-80] to [I-92], wherein the rate of addition of the base in step ii is 0.03 moles / hour to 0.5 moles / hour per mole of the compound of formula (7).

[0144] [I-102] A method according to any one of [I-80] to [I-92], wherein the rate of hydrogen peroxide addition in step ii is 0.13 moles / hour to 1.0 moles / hour per mole of compound (7).

[0145] [I-103] A method according to any one of [I-80] to [I-92], wherein the rate of addition of the oxidizing agent in step ii is 1 to 30 times (preferably more than 1 and 30 times or less) the rate of addition of the base in step ii.

[0146] [I-104] A method according to any one of [I-80] to [I-92], wherein the rate of addition of the oxidizing agent in step ii is 1 to 20 times (preferably more than 1 and 20 times or less) the rate of addition of the base in step ii.

[0147] [I-105] A method according to any one of [I-80] to [I-92], wherein the rate of addition of the oxidizing agent in step ii is 1 to 10 times (preferably more than 1 and 10 times or less) the rate of addition of the base in step ii.

[0148] 〔I-106〕 A method according to any one of claims [I-80] to [I-92], wherein the addition rate of the base in step ii is the same as the addition rate of the oxidizing agent in step ii.

[0149] 〔I-107〕 A method according to any one of claims [I-80] to [I-92], wherein the addition rate of the oxidizing agent in step ii is faster than the addition rate of the base in step ii.

[0150] 〔I-108〕 A method according to any one of claims [I-80] to [I-107], wherein the addition time of the base in step ii is from 1 hour to 48 hours.

[0151] 〔I-109〕 A method according to any one of claims [I-80] to [I-107], wherein the addition time of the base in step ii is from 1 hour to 24 hours.

[0152] 〔I-110〕 A method according to any one of claims [I-80] to [I-107], wherein the addition time of the oxidizing agent in step ii is from 1 hour to 48 hours.

[0153] 〔I-111〕 A method according to any one of claims [I-80] to [I-107], wherein the addition time of the oxidizing agent in step ii is from 1 hour to 24 hours.

[0154] 〔I-112〕 A method according to any one of claims [I-80] to [I-107], wherein the aging time after the addition of the base and the oxidizing agent in step ii is from 0.1 hour to 12 hours. <000091​​​​​​​

[0157] [I-115] A method according to any one of [I-80] to [I-114], wherein the reaction in step ii is carried out in the presence of a nitrile compound.

[0158] [I-116] A method according to [I-115], wherein the nitrile compound in step ii is an alkylnitrile derivative, a benzonitrile derivative, or a mixture thereof.

[0159] [I-117] A method according to [I-115], wherein the nitrile compound in step ii is acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile, benzonitrile, p-nitrobenzonitrile, or a mixture thereof.

[0160] [I-118] A method according to [I-115], wherein the nitrile compound in step ii is acetonitrile, isobutyronitrile, succinonitrile, benzonitrile, p-nitrobenzonitrile, or a mixture thereof.

[0161] [I-119] A method according to [I-115], wherein the nitrile compound in step ii is acetonitrile.

[0162] [I-120] A method according to any one of [I-115] to [I-119], wherein the amount of nitrile compound used in step ii is 1 to 100 moles (preferably 1 to 50 moles) per mole of compound of formula (7).

[0163] [I-121] A method according to any one of [I-115] to [I-119], wherein the amount of nitrile compound used in step ii is 1 to 35 moles per mole of the compound of formula (7).

[0164] [I-122] A method according to any one of [I-80] to [I-121], wherein the reaction in step ii is carried out in the presence of a ketone compound.

[0165] [I-123] The method according to [I-122], wherein the ketone compound in step ii is 2,2,2-trifluoroacetophenone.

[0166] [I-124] A method according to [I-122] or [I-123], wherein the amount of ketone compound used in step ii is 0.01 to 1.0 moles per mole of compound of formula (7).

[0167] [I-125] A method according to [I-122] or [I-123], wherein the amount of ketone compound used in step ii is 0.05 to 0.8 moles per mole of compound of formula (7).

[0168] [I-126] A method according to either item [I-122] or [I-123], wherein the amount of ketone compound used in step ii is 0.1 to 0.6 moles per mole of compound of formula (7).

[0169] [I-127] A method according to any one of [I-80] to [I-126], wherein the reaction in step ii is carried out in the presence of an organic solvent.

[0170] [I-128] A method according to [I-127], wherein the organic solvent for the reaction in step ii is selected from aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, alcohols, nitriles, carboxylic acid esters, ethers, ketones, amides, and ureas.

[0171] [I-129] A method according to [I-127] wherein the organic solvent in the reaction of step ii is one or more (preferably one or two, more preferably one) organic solvents selected from aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, alcohols, nitriles, carboxylic acid esters, ethers, ketones, amides, and ureas.

[0172] The method according to [I-130], [I-127], wherein the organic solvent for the reaction in step ii is one or more (preferably 1 or 2, more preferably 1) organic solvents selected from alcohols, nitriles, carboxylic acid esters, and amides.

[0173] The method according to [I-131], [I-127], [I-54], [I-50], wherein the organic solvent for the reaction in step ii is one or more (preferably 1 or 2, more preferably 1) organic solvents selected from alcohols, nitriles, and carboxylic acid esters.

[0174] The method according to [I-132], [I-127], wherein the organic solvent for the reaction in step ii is selected from alcohols, nitriles, and amides.

[0175] The method according to [I-133], [I-127], wherein the organic solvent for the reaction in step ii is one or more (preferably 1 or 2, more preferably 1) organic solvents selected from alcohols, nitriles, and amides.

[0176] The method according to [I-134], [I-127], wherein the organic solvent for the reaction in step ii is one or more (preferably 1 or 2, more preferably 1) organic solvents selected from the group consisting of methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, pentanol, sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile, benzonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0177] The method according to [I-135], [I-127], wherein the organic solvent for the reaction in step ii is one or more (preferably 1 or 2, more preferably 1) organic solvents selected from nitriles and amides.

[0178] [I-136] A method according to [I-127], wherein the organic solvent in the reaction of step ii is one or more (preferably one or two, more preferably one) organic solvents selected from the group consisting of acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile, benzonitrile, N,N-dimethylformamide and N,N-dimethylacetamide.

[0179] [I-137] A method according to [I-127], wherein the organic solvent in step ii of the reaction is a nitrile.

[0180] [I-138] The method according to [I-127], wherein the organic solvent for the reaction in step ii is selected from the group consisting of acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile, and benzonitrile.

[0181] [I-139] The method according to [I-127], wherein the organic solvent in the reaction of step ii is one or more organic solvents selected from the group consisting of niacetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile and benzonitrile.

[0182] [I-140] A method according to [I-127], wherein the organic solvent for the reaction in step ii is one or two organic solvents selected from the group consisting of acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile, and benzonitrile.

[0183] [I-141] The method according to [I-127], wherein the organic solvent for the reaction in step ii is one organic solvent selected from the group consisting of acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile and nzzonitrile.

[0184] [I-142] The method according to [I-127], wherein the organic solvent in step ii of the reaction is acetonitrile.

[0185] [I-143] A method according to any one of [I-127] to [I-142], wherein the amount of organic solvent used in the reaction of step ii is 0.5 to 3 liters (preferably 1 to 3 liters) per mole of the compound of formula (7).

[0186] [I-144] A method according to any one of [I-127] to [I-142], wherein the amount of organic solvent used in the reaction of step ii is 1 to 2 liters per mole of the compound of formula (7).

[0187] [I-145] A method according to [I-80] to [I-144], wherein the reaction in step ii is carried out in the presence of an aqueous solvent.

[0188] [I-146] A method according to [I-145], wherein the amount of aqueous solvent used in the reaction of step ii is 0.5 to 2.0 liters (preferably 0.8 to 1.5 liters) per mole of the compound of formula (7).

[0189] [I-147] A method according to [I-145] or [I-146], wherein the amount of aqueous solvent in the total solvent, which consists of an organic solvent and an aqueous solvent, is 20 to 60 vol% (preferably 30 to 50 vol%) of the total amount of the solvent.

[0190]

[0191] [I-148] A method according to any one of [I-80] to [I-147], wherein the reaction in step ii is carried out at 0°C to 80°C.

[0192] [I-149] A method according to any one of [I-80] to [I-147], wherein the reaction in step ii is carried out at 5°C to 60°C (preferably 10°C to 40°C).

[0193] [I-150] A method according to any one of [I-80] to [I-147], wherein the reaction in step ii is carried out for 5 minutes to 48 hours (preferably 10 minutes to 24 hours).

[0194] [I-151] A method according to any one of [I-1] to [I-4], wherein step ii is a method in which the reaction of formula (7) is reacted with an oxidizing agent under acidic conditions, and then reacted with an oxidizing agent under neutral to alkaline conditions.

[0195] [I-152] The method according to any one of [I-1] to [I-4], wherein the reaction in step ii includes the method according to any one of [I-5] to [I-79] and the method according to any one of [I-80] to [I-150].

[0196] [I-153] A method according to any one of [I-1] to [I-152], wherein the oxidizing agent in step ii is hydrogen peroxide, a persulfate, or a hydrogen persulfate.

[0197] [I-154] A method according to any one of [I-1] to [I-152], wherein the oxidizing agent in step ii is hydrogen peroxide.

[0198] [I-155] A method according to any one of [I-1] to [I-152], wherein the oxidizing agent in step ii is an alkali metal persulfate, an ammonium persulfate, or an alkali metal persulfate.

[0199] [I-156] A method according to any one of [I-1] to [I-152], wherein the oxidizing agent in step ii is sodium bisulfate, potassium bisulfate, potassium persulfate, sodium persulfate, or ammonium persulfate.

[0200] [I-157] A method according to any one of items [I-1] to [I-152], wherein the oxidizing agent in step ii is potassium persulfate.

[0201] [I-158] A method according to [I-153] to [I-157], wherein the organic solvent in step ii of the reaction is a nitrile or an amide (preferably acetonitrile or N,N-dimethylformamide).

[0202] [I-159] A method according to [I-153] to [I-157], wherein the organic solvent in step ii is a nitrile.

[0203] [I-160] A method according to [I-153] to [I-157], wherein the organic solvent in step ii is acetonitrile.

[0204] [I-161] A method according to any one of [I-153] to [I-160], wherein the amount of organic solvent used in the reaction of step ii is 0.3 to 1.3 liters (preferably 0.7 to 1.0 liter) per mole of the compound of formula (7).

[0205] [I-162] A method according to [I-153] to [I-161], wherein the reaction in step ii is carried out in the presence of an aqueous solvent.

[0206] [I-163] A method according to [I-162], wherein the amount of aqueous solvent used in the reaction of step ii is 1.0 to 4.0 liters (preferably 2.0 to 3.0 liters) per mole of the compound of formula (7).

[0207] [I-164] A method according to [I-162] or [I-163], wherein the amount of water in the total solvent, which consists of an organic solvent and an aqueous solvent, is 65 to 85 vol% (preferably 70 to 80 vol%) of the total amount of the solvent.

[0208] [I-165] A method according to any one of [I-153] to [I-164], wherein the reaction in step ii is carried out at 20°C to 100°C.

[0209] [I-166] A method according to any one of [I-153] to [I-164], wherein the reaction in step ii is carried out at 30°C to 90°C.

[0210] [I-167] A method according to any one of [I-153] to [I-166], wherein the reaction in step ii is carried out over a period of 1 to 48 hours.

[0211] [I-168] A method according to any one of [I-153] to [I-166], wherein the reaction in step ii is carried out over 1 to 24 hours.

[0212] [I-169] A method according to any one of items [I-1] to [I-168], wherein the oxidizing agent in step ii is a 10-70 wt% aqueous hydrogen peroxide solution, excluding methods in which the oxidizing agent is not hydrogen peroxide.

[0213] [I-170] A method according to any one of items [I-1] to [I-168], wherein the oxidizing agent in step ii is a 25-65 wt% aqueous hydrogen peroxide solution, excluding methods in which the oxidizing agent is not hydrogen peroxide.

[0214] [I-171] A method according to any one of [I-1] to [I-170], wherein the amount of oxidizing agent used in step ii is 2 to 8 moles (preferably 2 to 6 moles) per mole of the compound of formula (7).

[0215] [I-172] A method according to any one of [I-1] to [I-170], wherein the amount of oxidizing agent used in step ii is 2 to 5 moles (preferably 2 to 4 moles) per mole of the compound of formula (7).

[0216] [I-173] A method according to any one of [I-1] to [I-170], wherein the amount of oxidizing agent used in step ii is 3 to 6 moles per mole of the compound of formula (7).

[0217] [I-174] A method according to any one of [I-1] to [I-170], wherein the amount of oxidizing agent used in step ii is 1.0 to 2.0 moles (preferably 1.0 to 1.5 moles) per mole of the compound of formula (7).

[0218] [I-175] A method according to any one of [I-1] to [I-170], wherein the amount of oxidizing agent used in step ii is 1.0 to 1.5 moles per mole of the compound of formula (7).

[0219] [I-176] A method according to any one of the items [I-1] to [I-175], wherein an unimmobilized acidic compound is removed.

[0220] [I-178] A method of any one of the items [I-1] to [I-175], except that which is not fixed.

[0221] [I-176] A method according to any one of the items [I-1] to [I-175], In equations (7) and (8), R 1 is (C1-C4) alkyl, R 2 is a (C1-C4) perfluoroalkyl group, R 3 (C1-C4) alkyl which may be substituted with 1 to 9 fluorine atoms, R 4 and R 5 However, each component is independently (C1-C4) alkyl.

[0222] [I-177] A method according to any one of the items [I-1] to [I-175], In equations (7) and (8), R 1 It is methyl, R 2 It is trifluoromethyl, R 3 It is difluoromethyl, R 4 and R5 How is it methyl?

[0223] In another embodiment, the present invention is as follows:

[0224] [II-1] A method according to any one of [I-1] to [I-175], the method comprising the following step ia before step ii: (Step ia) In the presence of a base, the compound of formula (1) is reacted with the compound of formula (2) to produce the compound of formula (7);

[0225] [ka]

[0226] (In formula (1), R 1 , R 2 and R 3 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents. X 1 is a leaving group, In formula (2), R 4 and R 5 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; a (C1-C6) alkoxy which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents; or R 4 and R 5Together with the carbon atoms to which they are attached, they form a 4- to 12-membered carbon ring, which may be substituted by one or more substituents. X 2 is an atom or atomic group that forms an acid. In formula (7), R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.).

[0227] 〔II-2〕 A method according to any one of 〔I-1〕 to 〔I-175〕, which includes the following step i-b before step ii: (Step i-b) Reacting a compound of formula (4) with a compound of formula (3) in the presence of a base to produce a compound of formula (7);

[0228]

Chemical formula

[0229] (In formula (3), formula (4) and formula (7), R[[ID=3;5]] 1 , R 2 , R 3 , R 4 and R 5 are as defined above, X 4 is a leaving group.).

[0230] 〔II-3〕 A method according to any one of 〔I-1〕 to 〔I-175〕, which includes the following step i-c before step ii: (Step i-c) Reacting a compound of formula (5) with a compound of formula (6) in the presence of a base to produce a compound of formula (7);

[0231] ]

Chemical formula

[0232] [II-4] A method according to any one of [II-1] to [II-3], wherein the base of step ia, ib, or ic is an alkali metal hydroxide, an alkali metal carbonate, or a mixture thereof.

[0233] [II-5] A method according to any one of [II-1] to [II-3], wherein the base of step ia, ib, or ic is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or a mixture thereof.

[0234] [II-6] A method according to any one of the items [II-1] to [II-3], wherein the base of step ia, ib, or ic is an alkali metal hydroxide.

[0235] [II-7] A method according to any one of the items [II-1] to [II-3], wherein the base of step ia, ib, or ic is sodium hydroxide or potassium hydroxide.

[0236] [II-8] A method according to any one of the items [II-1] to [II-3], wherein the base of step ia, ib, or ic is an alkali metal carbonate.

[0237] [II-9] A method according to any one of the items [II-1] to [II-3], wherein the base of step ia, ib, or ic is potassium carbonate or sodium carbonate.

[0238] [II-10] A method according to any one of [II-1] to [II-9], wherein the reaction of step ia, ib, or ic is carried out in the presence of a solvent.

[0239] [II-11] A method according to [II-10], wherein the organic solvent in the reaction of step ia, ib, or ic is aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, alcohols, nitriles, carboxylic acid esters, ethers, ketones, amides, ureas, sulfoxides, sulfones, water, or a mixture thereof.

[0240] [II-12] A method according to [II-10], wherein the organic solvent in the reaction of step ia, ib, or ic is an alcohol, a nitrile, a carboxylic acid ester, an ether, an amide, a sulfone, water, or a mixture thereof.

[0241] [II-13] A method according to any one of [II-10] to [II-12], wherein the amount of solvent used in the reaction of step ia, ib, or ic is 1 to 3 liters per mole of the compound of formula (1), formula (4), or formula (5) for each reaction.

[0242] [II-14] A method according to any one of [II-10] to [II-12], wherein the total amount of solvent used in the reaction of step ia, ib, or ic is 1.5 to 3.0 liters per mole of the compound of formula (1), formula (4), or formula (5) for each reaction.

[0243] [II-15] A method according to any one of [II-10] to [II-12], wherein the total amount of solvent used in the reaction of step ia, ib, or ic is 1.5 to 2.5 liters per mole of the compound of formula (1), formula (4), or formula (5) for each reaction.

[0244] [II-16] A method according to any one of [II-10] to [II-12], wherein the total amount of solvent used in the reaction of step ia, ib, or ic is 1.7 to 2.0 liters per mole of the compound of formula (1), formula (4), or formula (5) for each reaction.

[0245] [II-17] A method according to any one of [II-1] to [II-16], wherein the reaction of step ia, ib, or ic is carried out at -10°C to 100°C.

[0246] [II-18] A method according to any one of [II-1] to [II-16], wherein the reaction of step ia, ib, or ic is carried out at -10°C to 70°C.

[0247] [II-19] A method according to any one of [II-1] to [II-16], wherein the reaction of step ia, ib, or ic is carried out at -10°C to 50°C.

[0248] [II-20] A method according to any one of [II-1] to [II-16], wherein the reaction of step ia, ib, or ic is carried out at 0°C to 40°C.

[0249] [II-21] A method according to any one of [II-1] to [II-16], wherein the reaction of step ia, ib, or ic is carried out at 0°C to 30°C.

[0250] [II-22] A method according to any one of items [II-1] to [II-21], wherein the reaction of step ia, ib, or ic is carried out over a period of 1 to 48 hours.

[0251] [II-23] A method according to any one of items [II-1] to [II-21], wherein the reaction of step ia, ib, or ic is carried out over a period of 1 to 24 hours.

[0252] [II-24] A method according to any one of items [II-1] to [II-21], wherein the reaction of step ia, ib, or ic is carried out over 4 to 24 hours.

[0253] [II-25] The method described in [II-1], wherein in formula (1), R 1 is (C1-C4) alkyl, R2 is (C1-C4) perfluoroalkyl, R 3 is (C1-C4) alkyl optionally substituted by 1 to 9 fluorine atoms, X 1 is a chlorine atom or a bromine atom, In formula (2), R 4 and R 5 are each independently (C1-C4) alkyl, X 2 is a chlorine atom, a bromine atom, a sulfate group, a hydrogen sulfate group, a phosphate group, a hydrogen phosphate group, methanesulfonyloxy, p-toluenesulfonyloxy or a mixture of two or more thereof. In formula (7), R 1 、R 2 、R 3 、R 4 and R 5 are as defined above.

[0254] 〔II-26〕 The method according to 〔II-1〕, wherein in formula (1), R 1 is methyl, R 2 is trifluoromethyl, R 3 is difluoromethyl, X 1 is a chlorine atom, In formula (2), R 4 and R 5 are methyl, X 2 is a chlorine atom, a bromine atom or a mixture thereof, In formulas (7) and formula ((8), R 1 、R 2 、R 3 、R 4 and R 5 are as defined above.

[0255] 〔II-27〕 The method according to 〔II-2〕, wherein in formula (3), R 3(C1-C4) alkyl which may be substituted with 1 to 9 fluorine atoms, X 4 is a chlorine atom or a bromine atom, In formula (4), R 1 is (C1-C4) alkyl, R 2 is a (C1-C4) perfluoroalkyl group, R 4 and R 5 However, each is independently a (C1-C4) alkyl group, In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5 This is the method as defined above.

[0256] [II-28] The method described in [II-2], wherein in formula (3), R 3 It is difluoromethyl, X 4 is a chlorine atom or a bromine atom, In formula (4), R 1 It is methyl, R 2 It is trifluoromethyl, R 4 and R 5 It is methyl, In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5 This is the method as defined above.

[0257] [II-29] The method described in [II-3], In formula (5), R 1 is (C1-C4) alkyl, R 2 is a (C1-C4) perfluoroalkyl group, R 3(C1-C4) alkyl which may be substituted with 1 to 9 fluorine atoms, X 5 is a chlorine atom, a bromine atom, or a mixture thereof, In formula (6), R 4 and R 5 However, each is independently a (C1-C4) alkyl group, X 3 is a chlorine atom or a bromine atom, In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5 This is the method as defined above.

[0258] [II-30] The method described in [II-3], In formula (5), R 1 It is methyl, R 2 It is trifluoromethyl, R 3 It is difluoromethyl, X 5 is a chlorine atom, a bromine atom, or a mixture thereof, in formula (6), R 4 and R 5 It is methyl, X 3 is a chlorine atom or a bromine atom, In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5 This is the method as defined above.

[0259] [III-1] A method for producing the compound of formula (8), comprising the following step ii: (Step ii) In the absence of a transition metal and in the presence of a base, the compound of formula (7) is reacted with an oxidizing agent to produce the compound of formula (8);

[0260] [ka] (In equations (7) and (8), R 1 , R 2 and R 3 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents. R 4 and R 5 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; a (C1-C6) alkoxy which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents; or R 4 and R 5 These atoms, together with the carbon atoms to which they are bonded, form a 4- to 12-membered carbon ring, which may be substituted with one or more substituents.

[0261] [III-2] The method according to [III-1], wherein the reaction in step ii is carried out in the presence of an organic solvent, wherein the organic solvent is an organic solvent other than alcohols.

[0262] [III-3] A method according to [III-1] or [III-2], wherein the organic solvent is acetonitrile.

[0263] [III-4] A method according to any one of [III-1] to [III-3], comprising the simultaneous addition of the base of step ii and the oxidizing agent of step ii.

[0264] [III-5] A method according to any one of items [III-1] to [III-4], wherein the base in step ii is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

[0265] [III-6] A method according to any one of items [III-1] to [III-5], wherein the oxidizing agent in step ii is hydrogen peroxide.

[0266] [III-7] A method for producing the compound of formula (8), comprising the following step ii: (Step ii) In the absence of a transition metal and in the presence of an acidic compound, the compound of formula (7) is reacted with an oxidizing agent to produce the compound of formula (8), where the acidic compound is sulfuric acid;

[0267] [ka] (In equations (7) and (8), R 1 , R 2 and R 3 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents. R 4 and R 5 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; a (C1-C6) alkoxy which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents; or R 4 and R 5 These atoms, together with the carbon atoms to which they are bonded, form a 4- to 12-membered carbon ring, which may be substituted with one or more substituents.

[0268] [III-8] A method according to [III-7], wherein the reaction of step ii is carried out in the presence of an organic solvent having an acceptor number of 5 to 25 and a relative permittivity of 1 to 40.

[0269] [III-9] A method according to [III-7], wherein the reaction of step ii is carried out in the presence of an organic solvent having 5 to 25 acceptors and 1 to 7 Rohrschneider polarity parameters.

[0270] [III-10] A method according to any one of items [III-7] to [III-9], wherein the organic solvent is an organic solvent other than alcohols.

[0271] [III-11] A method according to any one of items [III-7] to [III-10], wherein the organic solvent is selected from aromatic hydrocarbon derivatives, nitriles, carboxylic acid esters, and amides.

[0272] [III-12] A method according to any one of items [III-7] to [III-11], wherein the oxidizing agent in step ii is hydrogen peroxide.

[0273] [III-13] A method for producing the compound of formula (8), comprising the following step ii: (step ii) In the absence of a transition metal and in the presence of an acidic compound, the compound of formula (7) is reacted with an oxidizing agent to produce the compound of formula (8), wherein the acidic compound is a (C2-C4) alkanoic acid substituted with 1 to 7 fluorine atoms;

[0274] [ka] (In equations (7) and (8), R 1 , R 2 and R 3 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents. R 4 and R 5 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; a (C1-C6) alkoxy which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents; or R 4 and R 5 These atoms, together with the carbon atoms to which they are bonded, form a 4- to 12-membered carbon ring, which may be substituted with one or more substituents.

[0275] [III-14] A method according to [III-13], wherein the (C2-C4) alkanoic acid substituted with 1 to 7 fluorine atoms is trifluoroacetic acid.

[0276] [III-15] A method according to [III-13] or [III-14], wherein the oxidizing agent in step ii is hydrogen peroxide.

[0277] [III-16] A method for producing the compound of formula (8), comprising the following step ii: (step ii) Reacting the compound of formula (7) with an oxidizing agent in the presence of an organic solvent and in the absence of a transition metal to produce the compound of formula (8), wherein the organic solvent is a (C1-C4) alkanoic acid;

[0278] [ka] (In equations (7) and (8), R 1 , R 2 and R 3 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents. R 4 and R 5 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; a (C1-C6) alkoxy which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents; or R 4 and R 5 These atoms, together with the carbon atoms to which they are bonded, form a 4- to 12-membered carbon ring, which may be substituted with one or more substituents.

[0279] [III-17] A method according to [III-16], wherein the (C1-C4) alkanoic acid is acetic acid.

[0280] [III-18] A method according to [III-16] or [III-17], wherein the oxidizing agent in step ii is hydrogen peroxide.

[0281] [III-19] A method for producing the compound of formula (8), comprising the following step ii: (step ii) Reacting the compound of formula (7) with an oxidizing agent in the absence of a transition metal to produce the compound of formula (8), wherein the oxidizing agent is an alkali metal persulfate, an ammonium persulfate, or an alkali metal persulfate;

[0282] [ka] (In equations (7) and (8), R 1 , R 2 and R 3 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents. R 4 and R 5 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; a (C1-C6) alkoxy which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents; or R 4 and R 5 These atoms, together with the carbon atoms to which they are bonded, form a 4- to 12-membered carbon ring, which may be substituted with one or more substituents.

[0283] [III-20] A method according to [III-19], wherein the oxidizing agent is sodium persulfate, potassium persulfate, potassium persulfate, sodium persulfate, or ammonium persulfate.

[0284] [III-21] The method according to [III-20], wherein the reaction in step ii is carried out in the presence of an organic solvent, wherein the organic solvent is acetonitrile.

[0285] [III-22] The method described in any one of the items [III-1] to [III-21], In equations (7) and (8), R 1 is (C1-C4) alkyl, R 2 is a (C1-C4) perfluoroalkyl group, R 3 (C1-C4) alkyl which may be substituted with 1 to 9 fluorine atoms, R 4 and R 5 However, each component is independently (C1-C4) alkyl.

[0286] [III-23] The method described in any one of the items [III-1] to [III-21], In equations (7) and (8), R 1 It is methyl, R 2 It is trifluoromethyl, R 3 It is difluoromethyl, R 4 and R 5 How is it methyl?

[0287] This section explains the symbols and terms used in this specification.

[0288] In this specification, the following abbreviations and prefixes may be used, and their meanings are as follows: Me: Methyl Et: Ethyl Pr, n-Pr, and Pr-n:propyl (i.e., n-propyl) i-Pr and Pr-i: Isopropyl Bu, n-Bu, and Bu-n:butyl (i.e., n-butyl) s-Bu and Bu-s:sec-butyl (i.e., secondary butyl) i-Bu and Bu-i: Isobutyl t-Bu and But-t:tert-butyl (i.e., tertiary butyl) Ph: Phenyl n-: normal s- and sec-: Secondary i- and iso-: iso t- and tert-: tertiary c- and cyc-: cyclo o-: Ortho m-: meta p-:para

[0289] The term "nitro" refers to the substituent "-NO2". The terms "cyano" or "nitrile" refer to the substituent "-CN". The term "hydroxy" refers to the substituent "-OH". The term "amino" refers to the substituent "-NH2".

[0290] (Ca-Cb) means that the number of carbon atoms is between a and b. For example, in "(C1-C4) alkyl," "(C1-C4)" means that the alkyl group has 1 to 4 carbon atoms, and "(C2-C5)" means that the alkyl group has 2 to 5 carbon atoms. The "(Ca-Cb)" that indicates the number of carbon atoms is sometimes written without parentheses as "Ca-Cb." Therefore, for example, in "C1-C4 alkyl," "C1-C4" means that the alkyl group has 1 to 4 carbon atoms.

[0291] In this specification, general terms such as “alkyl” are interpreted to include both straight-chain and branched-chain compounds such as butyl and tert-butyl. On the other hand, the specific term “butyl” refers to straight-chain “n-butyl” and not branched-chain “tert-butyl.” Branched-chain isomers such as “tert-butyl” are specifically referred to where intended.

[0292] Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.

[0293] (C1-C6) alkyl refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0294] (C1-C4) alkyl refers to a linear or branched alkyl group having 1 to 4 carbon atoms. Examples of (C1-C4) alkyl include appropriate examples from the (C1-C6) alkyl examples above.

[0295] (C3-C6) cycloalkyl refers to a cycloalkyl group having 3 to 6 carbon atoms. Examples of (C3-C6) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0296] (C2-C6) alkenyls refer to straight-chain or branched-chain alkenyls having 2 to 6 carbon atoms. Examples of (C2-C6) alkenyls include, but are not limited to, vinyl, 1-propenyl, isopropenyl, 2-propenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, and 1-hexenyl.

[0297] (C2-C6) alkynyl refers to a linear or branched alkynyl having 2 to 6 carbon atoms. Examples of (C2-C6) alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 2-butynyl, 3-butynyl, 1-pentynyl, and 1-hexynyl.

[0298] Examples of (C6-C10)aryl compounds are phenyl, 1-naphthyl, and 2-naphthyl.

[0299] (C1-C6) haloalkyl refers to a linear or branched alkyl group with 1 to 6 carbon atoms, substituted with 1 to 13 identical or different halogen atoms (where halogen atoms have the same meaning as defined above). Examples of (C1-C6) haloalkyls include fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chlorodifluoromethyl, bromodifluoromethyl, 2-fluoroethyl, 1-chloroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2-chloro-1-methylethyl, 2,2,3,3,3-pentafluoropropyl, and 2,2,2-trifluoro-1 This includes, but is not limited to, trifluoromethylethyl, heptafluoropropyl, 1,2,2,2-tetrafluoro-1-trifluoromethylethyl, 4-fluorobutyl, 4-chlorobutyl, 2,2,3,3,4,4,4-heptafluorobutyl, nonafluorobutyl, 1,1,2,3,3,3-hexafluoro-2-trifluoromethylpropyl, 2,2,2-trifluoro-1,1-di(trifluoromethyl)ethyl, undecafluoropentyl, tridecafluorohexyl, etc.

[0300] (C1-C4) perfluoroalkyl refers to a linear or branched alkyl group having 1 to 4 carbon atoms, in which all hydrogen atoms are replaced by fluorine atoms. Examples of (C1-C4) perfluoroalkyls include trifluoromethyl (i.e., -CF3), pentafluoroethyl (i.e., -CF2CF3), heptafluoropropyl (i.e., -CF2CF2CF3), 1,2,2,2-tetrafluoro-1-trifluoromethylethyl (i.e., -CF(CF3)2), nonafluorobutyl (i.e., -CF2CF2CF2CF3), 1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl (i.e., -CF(CF3)CF2CF3), 1,1,2,3,3,3-hexafluoro-2-trifluoromethylpropyl (i.e., -CF2CF(CF3)2), and 2,2,2-trifluoro-1,1-di(trifluoromethyl)ethyl (i.e., -C(CF3)3).

[0301] (C1-C6)alkoxy means (C1-C6)alkyl-O- (where the (C1-C6)alkyl portion has the same meaning as defined above). Examples of (C1-C6)alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.

[0302] (C1-C6) alcohols mean (C1-C6) alkyl-OH (where the (C1-C6) alkyl portion has the same meaning as defined above). Examples of (C1-C6) alcohols include, but are not limited to, methanol, ethanol, propanol (i.e., 1-propanol), 2-propanol, butanol (i.e., 1-butanol), sec-butanol, isobutanol, tert-butanol, pentanol (i.e., 1-pentanol), sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, hexanol (i.e., 1-hexanol), cyclohexanol, etc. Polyols having 1 to 6 carbon atoms, such as ethylene glycol, propylene glycol, and glycerol (e.g., diols, triols), are equivalents of (C1-C6) alcohols.

[0303] (C1-C4) alcohols mean (C1-C4) alkyl-OH (where the (C1-C4) alkyl portion has the same meaning as defined above). Examples of (C1-C4) alcohols include, but are not limited to, methanol, ethanol, propanol (i.e., 1-propanol), 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, etc. Polyols having 1 to 4 carbon atoms, such as ethylene glycol, propylene glycol, and glycerol (e.g., diols, triols), are equivalents of (C1-C4) alcohols.

[0304] (C2-C5) alkanenitrile means (C1-C4) alkyl-CN (where the (C1-C4) alkyl portion means a linear or branched alkyl having 1 to 5 carbon atoms. Examples of (C1-C5) alkyl include appropriate examples from the (C1-C6) alkyl examples above). Examples of (C2-C5) alkanenitrile include, but are not limited to, acetonitrile and propionitrile. In this specification, (C2-C5) alkanenitrile will also be written as C2-C5 alkanenitrile. C2 alkanenitrile is acetonitrile. In other words, acetonitrile is ethanenitrile according to IUPAC nomenclature and is a C2 alkanenitrile having 2 carbon atoms. Similarly, propionitrile is a C3 alkanenitrile.

[0305] Examples of (C1-C4)alkyl(C1-C4)carboxylates include ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and their isomers, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate and their isomers, preferably including but not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and their isomers. In this specification, (C1-C4)alkyl(C1-C4)carboxylate is also referred to as C1-C4 alkylC1-C4 carboxylate.

[0306] Examples of N,N-di((C1-C4)alkyl)(C1-C4) alkanamides include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N-diethylacetamide, and preferably N,N-dimethylformamide and N,N-dimethylacetamide, but are not limited to these. In this specification, N,N-di((C1-C4)alkyl)(C1-C4) alkanamide is also written as N,N-di(C1-C4 alkyl)C1-C4 alkanamide. N,N-di(C1 alkyl)C1 alkanamide is N,N-dimethylformamide. N,N-di(C1 alkyl)C2 alkanamide is N,N-dimethylacetamide.

[0307] (C1-C4) alkanoic acid means (C1-C3) alkyl-COOH and formic acid (HCOOH), i.e., (C1-C3) alkyl-C(=O)-OH and H--C(=O)-OH (where the (C0-C4) alkyl portion is understood in accordance with the similar definitions herein). Examples of (C1-C4) alkanoic acid include, but are not limited to, acetic acid and propionic acid, preferably acetic acid. In this specification, (C1-C4) carboxylic acid is also written as C1-C4 carboxylic acid. (C2-C4) alkanes substituted with 1 to 7 fluorine atoms refer to (C1-C3) alkyl-COOH groups in which 1 to 7 hydrogen atoms on a (C1-C3) alkyl group are substituted with fluorine atoms. Examples of (C2-C4) alkanes substituted with 1 to 7 fluorine atoms include monofluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, pentafluoropropionic acid, etc., preferably trifluoroacetic acid, but not limited to these. (C2-C4) alkanes substituted with 1 to 7 fluorine atoms are also written as C2-C4 alkanes substituted with 1 to 7 fluorine atoms.

[0308] Examples of (C1-C4)alkyl(C1-C4)alkylketones include, but are not limited to, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), and methyl isobutyl ketone (MIBK). In this specification, (C1-C4)alkyl(C1-C4)alkylketones are also referred to as C1-C4 alkylC1-C4 alkylketones.

[0309] Examples of (C1-C4) dihaloalkanes include, but are not limited to, dichloromethane and 1,2-dichloroethane. In this specification, (C1-C4) dihaloalkanes are also referred to as C1-C4 dihaloalkanes.

[0310] A cyclic hydrocarbon group refers to a monocyclic or polycyclic cyclic group in which all atoms constituting the ring are carbon atoms. In one embodiment, examples of cyclic hydrocarbon groups include, but are not limited to, aromatic or non-aromatic, monocyclic, bicyclic, or tricyclic cyclic hydrocarbon groups with 3 to 14 members (preferably 5 to 14 members, more preferably 5 to 10 members). In another embodiment, examples of cyclic hydrocarbon groups include, but are not limited to, aromatic or non-aromatic, monocyclic or bicyclic (preferably monocyclic) cyclic hydrocarbon groups with 4 to 8 members (preferably 5 to 6 members). Examples of cyclic hydrocarbon groups include, but are not limited to, cycloalkyl and aryl groups. Examples of cycloalkyl include the (C3-C6) cycloalkyl examples above. Aryl is an aromatic cyclic group among the cyclic hydrocarbon groups as defined above. Examples of aryl include the (C6-C10) aryl examples above. The cyclic hydrocarbon groups defined or exemplified above may, if possible, include non-condensed cyclic (e.g., monocyclic or spirocyclic) and condensed cyclic groups. The cyclic hydrocarbon groups defined or exemplified above may, if possible, be unsaturated, partially saturated, or saturated. The cyclic hydrocarbon groups defined or exemplified above are also called carbocyclic groups. A carbocyclic is a ring corresponding to the cyclic hydrocarbon group defined or exemplified above. Examples of carbocyclics include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, and cyclohexene.

[0311] In this specification, the term "substituents" in "may be substituted with one or more substituents" is not particularly limited, as long as they are chemically acceptable and exhibit the effects of the present invention.

[0312] In this specification, the term "may be substituted with one or more substituents" includes, but is not limited to, one or more substituents (preferably 1 to 3 substituents) independently selected from substituent group (a).

[0313] The substituent group (a) consists of halogen atoms, nitro, cyano, hydroxy, amino, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, phenyl, and phenoxy.

[0314] In addition, one or more substituents (preferably 1 to 3 substituents) independently selected from substituent group (a) may each be independently substituted by one or more substituents (preferably 1 to 3 substituents) independently selected from substituent group (b). Here, substituent group (b) is the same as substituent group (a).

[0315] Examples of "(C1-C6) alkyls which may be substituted with one or more substituents" include, but are not limited to, (C1-C6) haloalkyls, (C1-C4) perfluoroalkyls, and (C1-C4) alkyls which may be substituted with 1 to 9 fluorine atoms.

[0316] Examples of (C1-C4) alkyl groups that may be substituted with 1 to 9 fluorine atoms include, but are not limited to, fluoromethyl (i.e., -CH2F), difluoromethyl (i.e., -CHF2), trifluoromethyl (i.e., -CF3), 2-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,2-trifluoro-1-trifluoromethylethyl, heptafluoropropyl, 1,2,2,2-tetrafluoro-1-trifluoromethylethyl, 4-fluorobutyl, 2,2,3,3,4,4,4-heptafluorobutyl, nonafluorobutyl, 1,1,2,3,3,3-hexafluoro-2-trifluoromethylpropyl, and 2,2,2-trifluoro-1,1-di(trifluoromethyl)ethyl.

[0317] In this specification, substituents (e.g., R 1 , R 2 , R 3 , R 4 , R 5, X 1 , X 2 , X 3 , X 4 and X 5 The terms “as described herein” and similar terms used when referring to (etc.) are incorporated herein by reference to all definitions of substituents and, if any, all examples, preferred examples, more preferred examples, even more preferred examples and particularly preferred examples, etc.

[0318] In this specification, the non-restrictive term "comprise(s) / comprising" may be optionally replaced with the restrictive term "consist(s) of / consisting of".

[0319] Unless otherwise explicitly stated, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this disclosure belongs.

[0320] Unless otherwise indicated, figures representing characteristics such as quantities, sizes, concentrations, and reaction conditions used herein are understood to be modified by the term “approximately.” In some embodiments, disclosed figures are interpreted with respect to the reported number of significant figures and the application of common rounding techniques. In some embodiments, disclosed figures are interpreted to include errors that inevitably arise from the standard deviation observed in each test measurement method.

[0321] (process ia) Let's explain process ia.

[0322] Step ia involves reacting the compound of formula (1) with the compound of formula (2) in the presence of a base to produce the compound of formula (7);

[0323] [ka]

[0324] (In equations (1), (2), and (7), R 1 , R 2, R 3 , R 4 , R 5 , X 1 and X 2 (This is as defined above.)

[0325] The reaction in step ia is a condensation reaction.

[0326] (Raw material for process ia: compound of formula (1)) The compound of formula (1) is used as the raw material for step ia. The compound of formula (1) is a known compound, or can be produced from a known compound by a known method.

[0327] WO2007 / 094225A1 (Patent Document 5) is summarized below. For example, WO2007 / 094225A1 (Patent Document 5) discloses that the pyrazole derivative FMTP was produced from an acetoacetate ester derivative, as shown in the figure below. As shown in Example 1-1, the compound of formula (1-a) can be produced by chlorinating this pyrazole derivative.

[0328] [ka]

[0329] In formula (1), R 1 , R 2 and R 3 Each of these is independently an optionally substituted (C1-C6) alkyl, an optionally substituted (C3-C6) cycloalkyl, an optionally substituted (C2-C6) alkenyl, an optionally substituted (C2-C6) alkynyl, or an optionally substituted (C6-C10) aryl.

[0330] In formula (1), X 1 X is a leaving group. 1 This can be any atom or group of atoms, as long as it functions as a leaving group in the reaction of step ia.

[0331] From the perspective of yield, availability, price, and usefulness of the product, R in formula (1) 1 Preferred examples include (C1-C6)alkyl, more preferably (C1-C6)alkyl, even more preferably (C1-C4)alkyl, and particularly preferably methyl, which may be substituted with one or more substituents.

[0332] From the same viewpoint as above, R in equation (1) 2 Preferred examples include (C1-C6) alkyl, more preferably (C1-C6) haloalkyl, even more preferably (C1-C4) perfluoroalkyl, and particularly preferably trifluoromethyl, which may be substituted with one or more substituents.

[0333] From the same viewpoint as above, R in equation (1) 3 Preferred examples include (C1-C6) alkyl groups which may be substituted with one or more substituents, more preferably (C1-C6) haloalkyl groups, even more preferably (C1-C4) alkyl groups which may be substituted with 1 to 9 fluorine atoms, and particularly preferably difluoromethyl groups.

[0334] From the perspective of yield, availability, price, etc., X in equation (2) 1 Preferred examples include halogen atoms, (C1-C4) alkylsulfonyloxy, (C1-C4) haloalkylsulfonyloxy, benzenesulfonyloxy which may have (C1-C4) alkyl or halogen atoms, more preferably chlorine atoms, bromine atoms, iodine atoms, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-chlorobenzenesulfonyloxy, even more preferably chlorine atoms and bromine atoms, and particularly preferably chlorine atoms.

[0335] Furthermore, another method for preparing the compound of formula (1) is described in WO2004 / 013106A1 (Patent Document 2), Examples 13 and 14, which are shown below.

[0336] [ka]

[0337] [ka]

[0338] In formula (1), R 1 , R 2 , R 3 and X 1 This is as defined above. In equation (1), R 1 , R 2 , R 3 and X 1 Examples of good, good, better, and particularly good examples are as described above.

[0339] Particularly preferred specific examples of compounds of formula (1) are as follows:

[0340] [ka]

[0341] Specific examples of the compound of formula (1), and particularly preferred specific examples, are as described above.

[0342] (Raw material for process ia: compound of formula (2)) The compound of formula (2) is used as the raw material for process ia.

[0343] The compound of formula (2) is a known compound, or can be produced from a known compound by a known method. For example, the preparation of the compound of formula (2) can be carried out by the methods described in WO2006 / 068092A1 (Patent Document 6), JP2013-512201 (JP2013-512201A) (Patent Document 7) and WO2019 / 131715A1 (Patent Document 8), or by similar methods. Japanese Patent Publication No. 2013-512201 (JP2013-512201A), paragraph 0004 (US2012 / 264947A1, paragraph 0007) (Patent Document 7) discloses a method for producing raw materials used in the method described in WO2006 / 068092A1 (Patent Document 6), citing Japanese Patent Application Publication No. 2008-001597 (JP2008-001597A) and WO2006 / 038657A1. These are summarized in the figure below.

[0344] [ka]

[0345] In formula (2), R 4 and R 5 Each of these is independently a (C1-C6) alkyl which may be substituted with one or more substituents; a (C3-C6) cycloalkyl which may be substituted with one or more substituents; a (C2-C6) alkenyl which may be substituted with one or more substituents; a (C2-C6) alkynyl which may be substituted with one or more substituents; a (C1-C6) alkoxy which may be substituted with one or more substituents; or a (C6-C10) aryl which may be substituted with one or more substituents; or R 4 and R 5 These, together with the carbon atoms to which they are bonded, form a 4- to 12-membered carbon ring, and the carbon ring may be substituted with one or more substituents.

[0346] From the perspective of yield, availability, price, and usefulness of the product, R in equation (2) 4 and R 5Preferred examples include, independently, (C1-C6)alkyl, more preferably (C1-C6)alkyl, even more preferably (C1-C4)alkyl, and particularly preferably methyl, each of which may be substituted with one or more substituents.

[0347] X in equation (2) 2 HX is an atom or group of atoms that forms an acid. Therefore, HX 2 It is an acid.

[0348] From the perspective of yield, availability, price, and usefulness of the product, X in equation (2) 2 A preferred example is, Halogen atoms, sulfate groups, hydrogen sulfate groups, phosphate groups, monohydrogen phosphate groups, dihydrogen phosphate groups, (C1-C4) alkylsulfonyloxy, (C1-C4) haloalkylsulfonyloxy, benzenesulfonyloxy which may have (C1-C4) alkyl or halogen atoms, and mixtures of two or more (preferably two or three, more preferably two) thereof, more preferably chlorine atoms, bromine atoms, iodine atoms, sulfate groups, hydrogen sulfate groups, phosphate groups, monohydrogen phosphate groups, dihydrogen phosphate groups, methanesulfonyloxy, ethanesulfonyloxy , trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-chlorobenzenesulfonyloxy and mixtures of two or more (preferably two or three, more preferably two) thereof, more preferably chlorine atoms, bromine atoms, sulfate groups, hydrogen sulfate groups, phosphate groups, monohydrogen phosphate groups, methanesulfonyloxy, p-toluenesulfonyloxy and mixtures of two or more (preferably two or three, more preferably two) thereof, particularly preferably chlorine atoms, bromine atoms and mixtures thereof.

[0349] Particularly preferred specific examples of compounds of formula (2) are the following compounds (2-a), (2-b), and mixtures thereof.

[0350] [ka]

[0351] Furthermore, if "X2H" is a polyhydric acid such as sulfuric acid or phosphoric acid, the ratio of "X2 of the acid portion" to "(4,5-dihydroisoxazolo-3-yl)thiocarboxamidine portion of formula (2-1) below" can be a ratio corresponding to all possible valencies of the polyhydric acid, which is within the scope of the present invention.

[0352] [ka]

[0353] In other words, for example, the compound of formula (2-c) below is an equivalent of the compound of formula (2).

[0354] [ka]

[0355] In the reaction of step ia, the isothiouronium group in the compound of formula (2) is replaced by the corresponding thiol group and / or its salt (for example, generally, -S - Na + or -S - K + It was presumed that the compounds produced thiol groups and / or salts thereof, and / or analogs thereof, corresponding to the compound of formula (2), are equivalents of the compound of formula (2), and methods using these equivalents fall within the scope of the present invention as defined by the appended claims.

[0356] (Raw materials for process ia: Amount of compound from formula (2) used) The amount of formula (2) used in step ia can be any amount as long as the reaction proceeds. The amount of formula (2) used in step ia can be adjusted as appropriate by those skilled in the art. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, the amount of compound of formula (2) used in step ia is, for example, 0.5 to 2.0 moles or more, preferably 0.8 to 1.5 moles, more preferably 1.0 to 1.5 moles, and even more preferably 1.0 to 1.1 moles per mole of compound (starting material) of formula (1).

[0357] (Product of process ia: compound of formula (7))

[0358] The product of step ia is the compound of formula (7), which corresponds to the compound of formula (1) and the compound of formula (2) used as raw materials.

[0359] In formula (7), R 1 , R 2 and R 3 This is as defined in equation (1). In equation (7), R 4 and R 5 This is as defined in equation (2). In equation (7), R 1 , R 2 , R 3 , R 4 and R 5 The examples, preferred examples, more preferred examples, and particularly preferred examples are the same as those in formulas (1) and (2) above.

[0360] Particularly preferred specific examples of compounds of formula (7) are as follows:

[0361] [ka]

[0362] (Base of process ia) The reaction in step ia is carried out in the presence of a base. Any base may be used, as long as the reaction proceeds. Examples of bases in step ia include, but are not limited to, the following: Alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal bicarbonates (e.g., calcium bicarbonate, etc.) Ammonia, etc., phosphates (e.g., sodium phosphate, potassium phosphate, calcium phosphate, etc.), hydrogen phosphates (e.g., sodium hydrogen phosphate, potassium hydrogen phosphate, calcium hydrogen phosphate, etc.), amines (e.g., triethylamine, tributylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undeca-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine, 4-(dimethylamino)-pyridine (DMAP), etc.), ammonia, etc., and mixtures thereof.

[0363] From the viewpoint of yield, suppression of by-products, and economic efficiency, preferred examples of the base in step ia include alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and mixtures thereof; more preferably, alkali metal hydroxides, alkali metal carbonates, and mixtures thereof; even more preferably, alkali metal hydroxides.

[0364] From the same viewpoint as described above, preferred specific examples of the base in step ia include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and mixtures thereof, more preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate and mixtures thereof, even more preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and mixtures thereof, even more preferably sodium hydroxide, potassium hydroxide and mixtures thereof, particularly preferably sodium hydroxide.

[0365] The base in step ia may be used alone or in any combination of two or more bases in any proportion. The form of the base in step ia may be any form as long as the reaction proceeds. Examples of the form of the base in step ia include solid base and aqueous solutions of any concentration. Specific examples of the form of the base include, but are not limited to, flakes, pellets, beads, powder and 10-50% aqueous solutions, preferably 20-50% aqueous solutions (e.g., 25% sodium hydroxide aqueous solution and 48% sodium hydroxide aqueous solution, preferably 48% sodium hydroxide aqueous solution). The form of the base in step ia can be appropriately selected by those skilled in the art.

[0366] The amount of base used in step ia can be any amount as long as the reaction proceeds. The amount of base used in step ia can be adjusted as appropriate by those skilled in the art. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the amount of base used in step ia is, for example, 5 to 10 moles, preferably 5 to 8 moles, more preferably 5 to 7 moles, and even more preferably 5 to 6 moles per mole of compound (starting material) of formula (1). In another embodiment, for example, 1 to 15 moles, preferably 1 to 10 moles, more preferably 2 to 9 moles, even more preferably 4 to 8 moles, and even more preferably 5 to 6 moles per mole of compound (starting material) of formula (1).

[0367] (Reaction solvent for process ia) From the viewpoint of ensuring the smooth progress of the reaction, it is preferable to carry out the reaction in step ia in the presence of a solvent.

[0368] The solvent for step ia can be any solvent, as long as the reaction proceeds.

[0369] Examples of solvents for the reaction in step ia include, but are not limited to, the following: Aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene, nitrobenzene, etc.), halogenated aliphatic hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane (EDC), etc.), alcohols (e.g., methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol (tert-butanol is also called tert-butyl alcohol), pentanol, sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, hexanol, cyclohexanol, etc.), nitriles (e.g., acetonitrile, propionitrile, etc.), carboxylic acid esters (e.g., methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its Isomers, etc.), ethers (e.g., tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, etc.), ketones (e.g., acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), etc.), amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), etc.), ureas (e.g., N,N'-dimethylimidazolidinone (DMI), tetramethylurea, etc.), sulfoxides (e.g., dimethyl sulfoxide (DMSO), etc.), sulfones (e.g., sulfolane, etc.), water, and any combination thereof in any proportion. "2-propanol" is also called "isopropyl alcohol" or "isopropanol".

[0370] However, from the viewpoint of yield, suppression of by-products, and economic efficiency, preferred examples of solvents for the reaction in step ia include: any combination of one or more (preferably one or two, more preferably one) organic solvents selected from aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, alcohols, nitriles, carboxylic acid esters, ethers, ketones, amides, ureas, sulfoxides, and sulfones, and aqueous solvent in any proportion.

[0371] A more preferred example of the solvent for the reaction in step ia includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from alcohols, nitriles, carboxylic acid esters, ethers, amides, and sulfones, and aqueous solvent in any proportion.

[0372] A more preferred example of the solvent for the reaction in step ia includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from alcohols, nitriles, carboxylic acid esters, ethers, and amides, and aqueous solvent in any proportion.

[0373] A more preferred example of the solvent for the reaction in step ia includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from alcohols, nitriles, carboxylic acid esters, and amides, and aqueous solvent in any proportion.

[0374] A more preferred example of the solvent for the reaction in step ia includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from alcohols, nitriles, and carboxylic acid esters, and aqueous solvent in any proportion.

[0375] A more preferred example of the solvent for the reaction in step ia includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from nitriles and carboxylic acid esters, and aqueous solvent in any proportion.

[0376] In one embodiment, particularly preferred examples of the solvent for the reaction in step ia include any combination of nitriles and aqueous solvent in any proportion.

[0377] In another embodiment, particularly preferred examples of the solvent for the reaction in step ia include any combination of carboxylic acid esters and aqueous solvent in any proportion.

[0378] From the same viewpoint as above, preferred specific examples of solvents for the reaction in step ia are toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, pentanol, sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers (in the present invention, "isomer of butyl acetate" is equivalent to "butyl acetate"), tetrahydrofuran (THF), 1,4-dioxane, diisopropyl acetate The solution comprises any combination of one or more (preferably one or two, more preferably one) organic solvents selected from ter, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone (DMI), tetramethylurea, dimethyl sulfoxide (DMSO), and sulfolane, and an aqueous solvent in any proportion.

[0379] From the same viewpoint as above, more preferred specific examples of solvents for the reaction in step ia are toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers (in the present invention, "isomer of butyl acetate" is equivalent to "butyl acetate"), tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl The solution comprises any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methyl ether (CPME), methyl tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone (DMI), tetramethylurea, dimethyl sulfoxide (DMSO), and sulfolane, and an aqueous solvent in any proportion.

[0380] From the same viewpoint as above, more preferred specific examples of solvents for the reaction in step ia are toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, 2-propanol, butanol, tert-butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers (in the present invention, "isomers of butyl acetate" are equivalents of "butyl acetate"), tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPM E) comprises any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methyl tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone (DMI), tetramethylurea, dimethyl sulfoxide (DMSO), and sulfolane, in any proportions, and an aqueous solvent.

[0381] More preferred specific examples of solvents for the reaction in step ia include any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methanol, ethanol, 2-propanol, butanol, tert-butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and their isomers, and aqueous solvent in any proportion.

[0382] A more preferred specific example of the solvent for the reaction in step ia includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate, and aqueous solvent in any proportion.

[0383] A more preferred specific example of the solvent for the reaction in step ia includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from acetonitrile, ethyl acetate, isopropyl acetate, and butyl acetate, and an aqueous solvent in any proportion.

[0384] A more preferred specific example of the solvent for the reaction in step ia includes any combination of one or two (preferably one) organic solvents selected from acetonitrile and butyl acetate and an aqueous solvent in any proportion.

[0385] In one embodiment, particularly preferred specific examples of the solvent for the reaction in step ia include any combination of acetonitrile solvent and aqueous solvent in any proportion.

[0386] In another embodiment, particularly preferred specific examples of the solvent for the reaction in step ia include any combination of butyl acetate solvent and aqueous solvent in any proportion.

[0387] In either case, as long as the reaction proceeds, the solvent may be a single layer or separated into two layers.

[0388] The amount of solvent used in step ia of the reaction is described below. "Total amount of solvent used in the reaction" is the sum of the amounts of all organic solvents and water used in the reaction. This does not include organic solvents and water used in post-reaction workup (e.g., isolation, purification, etc.). "Organic solvents" used in the reaction include organic solvents in the starting material solution and the reactant solution. "Water solvents" used in the reaction include water in the starting material solution and the reactant solution (e.g., water in a 48% sodium hydroxide aqueous solution).

[0389] The total amount of solvent used in step ia is not particularly limited, as long as the reaction system can be sufficiently stirred. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the total amount of solvent used in step ia is, for example, 0.1 to 10 L, preferably 0.5 to 5 L, more preferably 1 to 5 L, even more preferably 1 to 3 L, and still more preferably 1 to 2 L per mole of compound (starting material) of formula (1). In another embodiment, the total amount of solvent used in step ia is, for example, 1.5 to 3.0 L, preferably 1.5 to 2.5 L, and more preferably 1.5 to 2.0 L per mole of compound (starting material) of formula (1). In yet another embodiment, the total amount of solvent used in step i is, for example, 1.7 to 3.0 L, preferably 1.7 to 2.5 L, and more preferably 1.7 to 2.0 L per mole of compound (starting material) of formula (1).

[0390] From the same viewpoint as above, in one embodiment, the amount of organic solvent used in the reaction of step ia is, for example, 0 to 5 L, preferably 0.4 to 2.0 L, more preferably 0.5 to 1.5 L, even more preferably 0.6 to 1.0 L, and still more preferably 0.7 to 0.9 L, per mole of compound (starting material) of formula (1). In another embodiment, the amount of organic solvent used in the reaction of step ia is, for example, 0.1 to 5 L, preferably 0.3 to 2.0 L, more preferably 0.4 to 1.5 L, even more preferably 0.5 to 1.0 L, and still more preferably 0.6 to 0.8 L, per mole of compound (starting material) of formula (1).

[0391] From the same viewpoint as above, the amount of aqueous solvent used in step ia of the reaction is, for example, 0.1 to 5 L (liters), preferably 0.5 to 2.0 L, more preferably 0.5 to 1.5 L, even more preferably 0.7 to 1.4 L, and even more preferably 0.9 to 1.2 L per mole of compound (raw material) of formula (1).

[0392] When using a combination of two or more organic solvents, the proportions of the two or more organic solvents may be any proportion, as long as the reaction proceeds.

[0393] When using a combination of organic solvent and aqueous solvent, the ratio of the organic solvent to the aqueous solvent can be any ratio, as long as the reaction proceeds.

[0394] (Reaction temperature of process ia) The reaction temperature of step ia is not particularly limited. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, the reaction temperature of step i is, for example, -10°C to 100°C, preferably -10°C to 70°C, more preferably -10°C to 50°C, even more preferably 0°C to 40°C, even more preferably 0°C to 30°C, and even more preferably 0°C to 25°C.

[0395] (Reaction time for process ia) The reaction time of step ia is not particularly limited. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the reaction time of step ia is, for example, 4 to 48 hours, preferably 4 to 24 hours, more preferably 4 to 18 hours, and even more preferably 4 to 12 hours. In another embodiment, the reaction time of step ia is, for example, 1 to 48 hours, preferably 1 to 24 hours, more preferably 3 to 18 hours, and even more preferably 3 to 12 hours. However, the reaction time can be appropriately adjusted by those skilled in the art.

[0396] (Preparation method for process ia) The order in which the compounds of formula (1), formula (2), base, solvent, etc., are added is not particularly limited. As long as the reaction proceeds, the order in which they are added does not matter. For example, the base may be added dropwise to a mixture containing the compounds of formula (1), formula (2), and solvent in the reaction vessel. Another example is to add the compound of formula (2), base, and solvent to the reaction vessel, and then add the compound of formula (1) dropwise. Yet another example is to add the base and solvent to the reaction vessel, and then add the compounds of formula (1) and formula (2) dropwise in sequence.

[0397] (Post-processing of step ia; isolation and / or purification) The compound of formula (7), particularly compound (7-a), which is a product of step ia, can be used as a raw material for step ii. The compound of general formula (7) obtained in step ia may be isolated and / or purified and used in the next step, or it may be used in the next step without isolation. Whether or not to perform post-processing (isolation and / or purification) can be appropriately determined by a person skilled in the art, depending on the purpose and circumstances.

[0398] The compound of formula (7), particularly compound (7-a), which is the target product of step ia, can be isolated and purified from the reaction mixture by methods known to those skilled in the art (e.g., extraction, washing, crystallization including recrystallization, crystal washing and / or other operations), improved methods thereof, and any combination thereof.

[0399] (Process ib) Let me explain process ib.

[0400] Step ib is the process of reacting the compound of formula (4) with the compound of formula (3) in the presence of a base to produce the compound of formula (7);

[0401] [ka]

[0402] (In equations (3), (4), and (7), R 1 , R 2 , R 3 , R 4 , R 5 and X 4 (This is as defined above.)

[0403] (Raw material for process ib: compound of formula (4)) The compound of formula (4) is used as a raw material for step ib. The compound of formula (4) is a known compound, or can be produced from a known compound according to a known method. For example, the preparation of the compound of formula (4) is described in WO2005 / 105755A1 (Patent Document 4), Reference Example 1, which are shown below.

[0404] [ka]

[0405] In formula (4), R 1 , R 2 , R 3 , R 3 and R 5 This is as defined above. In equation (4), R 1 , R 2 , R 3 , R 3 and R 5 Examples of good, good, better, and particularly good examples are as described above.

[0406] Particularly preferred specific examples of compounds of formula (4) are as follows:

[0407] [ka]

[0408] (Raw material for process ib: compound of formula (3)) The compound of formula (3) is used as a raw material for step ib. The compound of formula (3) is a known compound, or can be produced from a known compound by a known method.

[0409] In formula (3), R 3 As defined above, X 4 X is a leaving group. 4 This can be any atom or group of atoms, as long as it functions as a leaving group in the reaction of step ib.

[0410] From the perspective of yield, availability, price, etc., X in equation (3) 4Preferred examples include halogen atoms, (C1-C4) alkylsulfonyloxy, (C1-C4) haloalkylsulfonyloxy, benzenesulfonyloxy which may have (C1-C4) alkyl or halogen atoms, more preferably chlorine atoms, bromine atoms, iodine atoms, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-chlorobenzenesulfonyloxy, even more preferably chlorine atoms and bromine atoms, and particularly preferably chlorine atoms.

[0411] In formula (3), R 3 and X 4 This is as defined above. In equation (3), R 3 and X 4 Examples of good, good, better, and particularly good examples are as described above.

[0412] A particularly preferred specific example of the compound of formula (3) is chlorodifluoromethane.

[0413] (Base of process ib) The reaction in step ib is carried out in the presence of a base. Any base may be used, as long as the reaction proceeds. Examples of bases in step ib include, but are not limited to, the following: Alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal bicarbonates (e.g., calcium bicarbonate, etc.) Ammonia, etc., phosphates (e.g., sodium phosphate, potassium phosphate, calcium phosphate, etc.), hydrogen phosphates (e.g., sodium hydrogen phosphate, potassium hydrogen phosphate, calcium hydrogen phosphate, etc.), amines (e.g., triethylamine, tributylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undeca-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine, 4-(dimethylamino)-pyridine (DMAP), etc.), ammonia, etc., and mixtures thereof.

[0414] From the viewpoint of yield, suppression of by-products, and economic efficiency, preferred examples of the base in step ib include alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and mixtures thereof; more preferably, alkali metal hydroxides, alkali metal carbonates, and mixtures thereof; and even more preferably, alkali metal hydroxides.

[0415] From the same viewpoint as above, preferred specific examples of the base in step ib include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and mixtures thereof, more preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate and mixtures thereof, even more preferably sodium hydroxide, potassium hydroxide and mixtures thereof, particularly preferably sodium hydroxide.

[0416] The bases in step ib may be used alone or in any combination of two or more in any proportion. The form of the bases in step ib may be any form, as long as the reaction proceeds. Examples of the forms of the bases in step ib include solid bases and aqueous solutions of any concentration. Specific examples of the forms of the bases include, but are not limited to, flakes, pellets, beads, powders, and 10-50% aqueous solutions, preferably flakes, pellets, beads, powders, etc. A person skilled in the art can appropriately select the form of the bases in step ib.

[0417] The amount of base used in step ib can be any amount as long as the reaction proceeds. The amount of base used in step ib can be adjusted as appropriate by those skilled in the art. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, the amount of base used in step ib is, for example, 1 to 10 moles, preferably 1 to 8 moles, more preferably 2 to 6 moles, even more preferably 3 to 5 moles, and still more preferably 3 to 4 moles per mole of compound (starting material) of formula (4).

[0418] (Reaction solvent for step ib) From the viewpoint of ensuring the smooth progress of the reaction, it is preferable to carry out the reaction in step ib in the presence of a solvent. The solvent for step ib can be any solvent, as long as the reaction proceeds.

[0419] In one embodiment, examples of solvents for the reaction in step ib include, but are not limited to, any combination thereof in any proportion.

[0420] In another embodiment, examples of solvents for the reaction in step ib include, but are not limited to, the following: Aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene, nitrobenzene, etc.), halogenated aliphatic hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane (EDC), etc.), alcohols (e.g., methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol (tert-butanol is also called tert-butyl alcohol), pentanol, sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, hexanol, cyclohexanol, etc.), nitriles (e.g., acetonitrile, propionitrile, etc.), carboxylic acid esters (e.g., methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its Isomers, etc.), ethers (e.g., tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, etc.), ketones (e.g., acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), etc.), amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), etc.), ureas (e.g., N,N'-dimethylimidazolidinone (DMI), tetramethylurea, etc.), sulfoxides (e.g., dimethyl sulfoxide (DMSO), etc.), sulfones (e.g., sulfolane, etc.), water, and any combination thereof in any proportion. "2-propanol" is also called "isopropyl alcohol" or "isopropanol".

[0421] However, from the viewpoint of yield, suppression of by-products, and economic efficiency, preferred examples of solvents for the reaction in step ib include: any combination of one or more (preferably one or two, more preferably one) selected from aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, alcohols, nitriles, carboxylic acid esters, ethers, ketones, amides, ureas, sulfoxides, sulfones, and water.

[0422] A more preferred example of the solvent for the reaction in step ib includes any combination of one or more (preferably one or two, more preferably one) selected from alcohols, nitriles, carboxylic acid esters, ethers, amides, sulfones, and water.

[0423] A more preferred example of the solvent for the reaction in step ib includes any combination of one or more (preferably one or two, more preferably one) selected from nitriles, carboxylic acid esters, ethers, amides, and sulfoxides.

[0424] A more preferred example of the solvent for the reaction in step ib includes any combination of one or more (preferably one or two, more preferably one) selected from nitriles, carboxylic acid esters, amides, and sulfoxides.

[0425] A more preferred example of the solvent for the reaction in step ib includes any combination of one or more (preferably one or two, more preferably one) nitriles and amides selected from the nitriles and amides.

[0426] In one embodiment, particularly preferred examples of solvents for the reaction in step ib are nitriles.

[0427] From the same viewpoint as above, preferred specific examples of solvents for the reaction in step ib are toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, pentanol, sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers (in the present invention, "isomer of butyl acetate" is equivalent to "butyl acetate"), tetrahydrofuran (THF), 1,4-dioxane, diisopropyl The mixture comprises any combination of one or more (preferably one or two, more preferably one) selected from propyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone (DMI), tetramethylurea, dimethyl sulfoxide (DMSO), and sulfolane.

[0428] From the same viewpoint as above, more preferred specific examples of solvents for the reaction in step ib are toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers (in the present invention, "isomer of butyl acetate" is equivalent to "butyl acetate"), tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, sil The mixture comprises any combination of one or more (preferably one or two, more preferably one) selected from clopentyl methyl ether (CPME), methyl tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone (DMI), tetramethylurea, dimethyl sulfoxide (DMSO), and sulfolane.

[0429] From the same viewpoint as above, more preferred specific examples of solvents for the reaction in step ib are toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, 2-propanol, butanol, tert-butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers (in the present invention, "isomer of butyl acetate" is equivalent to "butyl acetate"), tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether The mixture comprises any combination of one or more (preferably one or two, more preferably one) selected from CPME, methyl tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone (DMI), tetramethylurea, dimethyl sulfoxide (DMSO), and sulfolane.

[0430] More preferred specific examples of solvents for the reaction in step ib include any combination of one or more (preferably one or two, more preferably one) selected from acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and their isomers.

[0431] More preferred specific examples of the solvent for the reaction in step ib include any combination of one or more (preferably one or two, more preferably one) selected from acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO).

[0432] More preferred specific examples of the solvent for the reaction in step ib include any combination of one or two (preferably one) selected from acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), and N-methylpyrrolidone (NMP) in any proportion.

[0433] In one embodiment, a particularly preferred specific example of the solvent for the reaction in step ib is acetonitrile solvent.

[0434] The amount of solvent used in step ib is explained below. The amount of solvent used in step ib is not particularly limited as long as the reaction system can be sufficiently stirred. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the total amount of solvent used in step ib is, for example, per mole of compound (starting material) of formula (4) The amount of organic solvent used in the reaction of step ib is, for example, 0.1 to 5 L, preferably 0.4 to 2.0 L, more preferably 0.5 to 1.5 L, even more preferably 0.6 to 1.0 L, for 1 mole of the compound (starting material) of formula (4), which is 0.1 to 5 L, preferably 0.3 to 2.0 L, more preferably 0.5 to 1.5 L, even more preferably 0.7 to 1.3 L, and even more preferably 0.8 to 1.2 L.

[0435] When using a combination of two or more organic solvents, the proportions of the two or more organic solvents may be any proportion, as long as the reaction proceeds.

[0436] (Reaction temperature of process ib) The reaction temperature of step ib is not particularly limited. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, the reaction temperature of step ib is, for example, -10°C to 100°C, preferably -10°C to 70°C, more preferably -10°C to 50°C, even more preferably 0°C to 40°C, even more preferably 0°C to 30°C, and even more preferably 0°C to 25°C.

[0437] (Reaction time for process ib) The reaction time of step ib is not particularly limited. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the reaction time of step ib is, for example, 1 to 48 hours, preferably 1 to 24 hours, more preferably 1 to 18 hours, and even more preferably 1 to 12 hours.

[0438] (Preparation method for process ib) The order in which the compounds of formula (4), formula (3), base, and solvent are added is not particularly limited. As long as the reaction proceeds, the order in which they are added does not matter. For example, the base may be added dropwise to a mixture containing the compound of formula (4), the compound of formula (3), and the solvent in the reaction vessel. Another example is to add the compound of formula (4), the base, and the solvent to the reaction vessel, and then introduce the compound of formula (3). Yet another example is to add the base and the solvent to the reaction vessel, and then sequentially introduce the compound of formula (3) and the compound of formula (4).

[0439] (process ic) I will explain the IC process.

[0440] Step ic is the process of reacting the compound of formula (5) with the compound of formula (6) in the presence of a base to produce the compound of formula (7);

[0441] [ka]

[0442] (In equations (5), (6), and (7), R 1 , R 2 , R 3 , R 4 , R 5 and X 3 As defined above, X 5 (A is an atom or group of atoms that forms an acid.)

[0443] (Raw material for process IC: compound of formula (5)) The compound of formula (5) is used as a raw material for process ic. The compound of formula (5) is a known compound, or can be produced from a known compound according to a known method. For example, the preparation of the compound of formula (5) is described in WO2004 / 013106A1 (Patent Document 2), Example 15, which are shown below.

[0444] [ka]

[0445] In formula (5), R 1 , R 2 , R 3 and X 5 This is as defined above. In equation (5), R 1 , R 2 and R 3 Examples, preferred examples, more preferred examples and particularly preferred examples are as shown above, X 5 Examples, preferred examples, more preferred examples and particularly preferred examples are X 2 They are the same as those.

[0446] Particularly preferred specific examples of compounds of formula (5) are as follows:

[0447] [ka]

[0448] In the reaction of step ic, the isothiouronium group in the compound of formula (5) corresponds to the thiol group and / or its salt (for example, generally -S - Na + or -S - K + It was presumed that the compounds produced thiol groups and / or salts thereof, and / or analogs thereof, corresponding to the compound of formula (5), are equivalents of the compound of formula (5), and methods using these equivalents fall within the scope of the present invention as defined by the appended claims.

[0449] (Raw material for process IC: compound of formula (6)) The compound of formula (6) is used as a raw material for process IC. The compound of formula (6) is a known compound, or can be produced from a known compound by a known method.

[0450] X in equation (6) 3 X is a leaving group. 3 This can be any atom or group of atoms, as long as it functions as a leaving group in the reaction of step IC.

[0451] From the standpoint of yield, availability, price, etc., X in equation (6) 3 Preferred examples include halogen atoms, (C1-C4) alkylsulfonyloxy, (C1-C4) haloalkylsulfonyloxy, benzenesulfonyloxy which may have an alkyl or halogen atom, more preferably chlorine atoms, bromine atoms, iodine atoms, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-chlorobenzenesulfonyloxy, and particularly preferably chlorine atoms and bromine atoms.

[0452] In formula (6), R 4 , R 5 and X 3 This is as defined above. In equation (6), R 4 , R 5 and X 3 Examples of good, good, better, and particularly good examples are as described above.

[0453] Particularly preferred specific examples of compounds of formula (6) are as follows:

[0454] [ka]

[0455] (Raw materials for process IC: Amount of compound of formula (5) used) The amount of formula (5) used in step ic can be any amount as long as the reaction proceeds. The amount of formula (5) used in step ic can be adjusted as appropriate by those skilled in the art. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, the amount of compound of formula (5) used in step ic is, for example, 0.5 to 2.0 moles or more, preferably 0.8 to 1.5 moles, more preferably 1.0 to 1.5 moles, and even more preferably 1.0 to 1.1 moles per mole of compound (raw material) of formula (5).

[0456] (Product of process ic: compound of formula (7))

[0457] The product of process ic is the compound of formula (7), which corresponds to the compound of formula (5) and the compound of formula (6) used as raw materials.

[0458] In formula (7), R 1 , R 2 , R 3 , R 4 and R 5 Examples are as shown above.

[0459] (Base of process IC) The reaction in step IC is carried out in the presence of a base. Any base may be used, as long as the reaction proceeds. Examples of bases in step IC include, but are not limited to, the following: Alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), alkaline earth metal bicarbonates (e.g., calcium bicarbonate, etc.) Ammonia, etc., phosphates (e.g., sodium phosphate, potassium phosphate, calcium phosphate, etc.), hydrogen phosphates (e.g., sodium hydrogen phosphate, potassium hydrogen phosphate, calcium hydrogen phosphate, etc.), amines (e.g., triethylamine, tributylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undeca-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine, 4-(dimethylamino)-pyridine (DMAP), etc.), ammonia, etc., and mixtures thereof.

[0460] From the viewpoint of yield, suppression of by-products, and economic efficiency, preferred examples of the base for process IC include alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and mixtures thereof; more preferably, alkali metal hydroxides, alkali metal carbonates, and mixtures thereof; and even more preferably, alkali metal hydroxides.

[0461] From the same viewpoint as above, preferred specific examples of the base of process IC include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and mixtures thereof, more preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate and mixtures thereof, even more preferably sodium hydroxide, potassium hydroxide and mixtures thereof, particularly preferably sodium hydroxide.

[0462] The bases in step IC may be used alone or in any combination of two or more in any proportion. The form of the bases in step IC may be any form as long as the reaction proceeds. Examples of the forms of the bases in step IC include solid bases and aqueous solutions of any concentration. Specific examples of the forms of the bases include, but are not limited to, flakes, pellets, beads, powders, and 10-50% aqueous solutions, preferably 20-50% aqueous solutions (e.g., 25% sodium hydroxide aqueous solution and 48% sodium hydroxide aqueous solution, preferably 48% sodium hydroxide aqueous solution). The form of the bases in step IC can be appropriately selected by those skilled in the art.

[0463] The amount of base used in step IC can be any amount as long as the reaction proceeds. The amount of base used in step IC can be adjusted as appropriate by those skilled in the art. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the amount of base used in step IC is, for example, 5 to 10 moles, preferably 5 to 8 moles, more preferably 5 to 7 moles, and even more preferably 5 to 6 moles per mole of compound (starting material) of formula (6). In another embodiment, for example, 1 to 15 moles, preferably 1 to 10 moles, more preferably 2 to 9 moles, even more preferably 4 to 8 moles, and even more preferably 5 to 6 moles per mole of compound (starting material) of formula (6).

[0464] (Reaction solvent for process IC) From the viewpoint of ensuring the smooth progress of the reaction, it is preferable to carry out step IC in the presence of a solvent. Any solvent may be used for step IC, as long as the reaction proceeds.

[0465] Examples of solvents for the reaction in step IC include, but are not limited to, the following: Aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene, nitrobenzene, etc.), halogenated aliphatic hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane (EDC), etc.), alcohols (e.g., methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol (tert-butanol is also called tert-butyl alcohol), pentanol, sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, hexanol, cyclohexanol, etc.), nitriles (e.g., acetonitrile, propionitrile, etc.), carboxylic acid esters (e.g., methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its Isomers, etc.), ethers (e.g., tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, etc.), ketones (e.g., acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), etc.), amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), etc.), ureas (e.g., N,N'-dimethylimidazolidinone (DMI), tetramethylurea, etc.), sulfoxides (e.g., dimethyl sulfoxide (DMSO), etc.), sulfones (e.g., sulfolane, etc.), water, and any combination thereof in any proportion. "2-propanol" is also called "isopropyl alcohol" or "isopropanol".

[0466] However, from the viewpoint of yield, suppression of by-products, and economic efficiency, preferred examples of solvents for the reaction in step IC include: any combination of one or more (preferably one or two, more preferably one) organic solvents selected from aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, alcohols, nitriles, carboxylic acid esters, ethers, ketones, amides, ureas, sulfoxides, and sulfones, and aqueous solvent in any proportion.

[0467] A more preferred example of the solvent for the reaction in step IC is a combination of one or more (preferably one or two, more preferably one) organic solvents selected from alcohols, nitriles, carboxylic acid esters, ethers, amides, and sulfones, and any proportion of aqueous solvent.

[0468] A more preferred example of the solvent for the reaction in step IC is a combination of one or more (preferably one or two, more preferably one) organic solvents selected from alcohols, nitriles, carboxylic acid esters, ethers, and amides, and any proportion of aqueous solvent.

[0469] A more preferred example of the solvent for the reaction in step IC is a combination of one or more (preferably one or two, more preferably one) organic solvents selected from alcohols, nitriles, carboxylic acid esters, and amides, and any proportion of aqueous solvent.

[0470] A more preferred example of the solvent for the reaction in step IC is a combination of one or more (preferably one or two, more preferably one) organic solvents selected from alcohols, nitriles, and carboxylic acid esters, and any proportion of aqueous solvent.

[0471] A more preferred example of the solvent for the reaction in step IC includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from nitriles and carboxylic acid esters, and aqueous solvent in any proportion.

[0472] In one embodiment, particularly preferred examples of the solvent for the reaction of step IC include any combination of nitriles and aqueous solvent in any proportion.

[0473] In another embodiment, particularly preferred examples of the solvent for the reaction of step IC include any combination of carboxylic acid esters and aqueous solvent in any proportion.

[0474] From the same viewpoint as above, preferred specific examples of solvents for the reaction in step IC are toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, pentanol, sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers (in the present invention, "isomer of butyl acetate" is equivalent to "butyl acetate"), tetrahydrofuran (THF), 1,4-dioxane, diisopropyl acetate The solution comprises any combination of one or more (preferably one or two, more preferably one) organic solvents selected from ter, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone (DMI), tetramethylurea, dimethyl sulfoxide (DMSO), and sulfolane, and an aqueous solvent in any proportion.

[0475] From the same viewpoint as above, more preferred specific examples of solvents for the reaction in step IC are toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers (in the present invention, "isomer of butyl acetate" is equivalent to "butyl acetate"), tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl The solution comprises any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methyl ether (CPME), methyl tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone (DMI), tetramethylurea, dimethyl sulfoxide (DMSO), and sulfolane, and an aqueous solvent in any proportion.

[0476] From the same viewpoint as above, more preferred specific examples of solvents for the reaction in step IC are toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, 2-propanol, butanol, tert-butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers (in the present invention, "isomer of butyl acetate" is equivalent to "butyl acetate"), tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPM E) comprises any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methyl tert-butyl ether, 1,2-dimethoxyethane (DME), diglyme, acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N,N'-dimethylimidazolidinone (DMI), tetramethylurea, dimethyl sulfoxide (DMSO), and sulfolane, in any proportions, and an aqueous solvent.

[0477] More preferred specific examples of solvents for the reaction in step IC include any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methanol, ethanol, 2-propanol, butanol, tert-butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and their isomers, and aqueous solvent in any proportion.

[0478] A more preferred specific example of the solvent for the reaction in step IC includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from butanol, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate, and aqueous solvent in any proportion.

[0479] A more preferred specific example of the solvent for the reaction in step IC includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from acetonitrile, ethyl acetate, isopropyl acetate, and butyl acetate, and an aqueous solvent in any proportion.

[0480] A more preferred specific example of the solvent for the reaction in step IC includes any combination of one or two (preferably one) organic solvents selected from acetonitrile and butyl acetate and an aqueous solvent in any proportion.

[0481] In one embodiment, particularly preferred specific examples of the solvent for the reaction of step IC include any combination of acetonitrile solvent and aqueous solvent in any proportion.

[0482] In another embodiment, particularly preferred specific examples of the solvent for the reaction of step IC include any combination of butyl acetate solvent and aqueous solvent in any proportion.

[0483] In either case, as long as the reaction proceeds, the solvent may be a single layer or separated into two layers.

[0484] This section describes the amount of solvent used in the reaction of step IC. "Total amount of solvent used in the reaction" is the sum of the amounts of all organic solvents and water used in the reaction. It does not include organic solvents and water used for post-reaction workup (e.g., isolation, purification, etc.). "Organic solvents" used in the reaction include organic solvents in the starting material solution and the reactant solution. "Water solvents" used in the reaction include water in the starting material solution and the reactant solution (e.g., water in a 48% sodium hydroxide aqueous solution).

[0485] The total amount of solvent used in step IC is not particularly limited, as long as the reaction system can be sufficiently stirred. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the total amount of solvent used in step IC is, for example, 0.1 to 10 L, preferably 0.5 to 5 L, more preferably 1 to 5 L, even more preferably 1 to 3 L, and still more preferably 1 to 2 L per mole of compound (starting material) of formula (6). In another embodiment, the total amount of solvent used in step IC is, for example, 1.5 to 3.0 L, preferably 1.5 to 2.5 L, and more preferably 1.5 to 2.0 L per mole of compound (starting material) of formula (6). In yet another embodiment, the total amount of solvent used in step IC is, for example, 1.7 to 3.0 L, preferably 1.7 to 2.5 L, and more preferably 1.7 to 2.0 L per mole of compound (starting material) of formula (6).

[0486] From the same viewpoint as above, in one embodiment, the amount of organic solvent used in the reaction of step ic is, for example, 0 to 5 L, preferably 0.4 to 2.0 L, more preferably 0.5 to 1.5 L, even more preferably 0.6 to 1.0 L, and still more preferably 0.7 to 0.9 L, per mole of compound (raw material) of formula (6). In another embodiment, the amount of organic solvent used in the reaction of step ic is, for example, 0.1 to 5 L, preferably 0.3 to 2.0 L, more preferably 0.4 to 1.5 L, even more preferably 0.5 to 1.0 L, and still more preferably 0.6 to 0.8 L, per mole of compound (raw material) of formula (6).

[0487] From the same viewpoint as above, the amount of aqueous solvent used in the reaction of step ic is, for example, 0.1 to 5 L (liters), preferably 0.5 to 2.0 L, more preferably 0.5 to 1.5 L, even more preferably 0.7 to 1.4 L, and even more preferably 0.9 to 1.2 L per mole of compound (raw material) of formula (6).

[0488] When using a combination of two or more organic solvents, the proportions of the two or more organic solvents may be any proportion, as long as the reaction proceeds.

[0489] When using a combination of organic solvent and aqueous solvent, the ratio of the organic solvent to the aqueous solvent can be any ratio, as long as the reaction proceeds.

[0490] (Reaction temperature of process IC) The reaction temperature of process IC is not particularly limited. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, the reaction temperature of process IC is, for example, -10°C to 100°C, preferably -10°C to 70°C, more preferably -10°C to 50°C, even more preferably 0°C to 40°C, even more preferably 0°C to 30°C, and even more preferably 0°C to 25°C.

[0491] (Process IC reaction time) The reaction time for step IC is not particularly limited. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the reaction time for step IC is, for example, 4 to 48 hours, preferably 4 to 24 hours, more preferably 4 to 18 hours, and even more preferably 4 to 12 hours. In another embodiment, the reaction time for step IC is, for example, 1 to 48 hours, preferably 1 to 24 hours, more preferably 3 to 18 hours, and even more preferably 3 to 12 hours. However, the reaction time can be appropriately adjusted by those skilled in the art.

[0492] (Preparation method for process ICs) The order in which the compounds of formula (5), formula (6), base, solvent, etc., are added is not particularly limited. As long as the reaction proceeds, the order in which they are added does not matter. For example, the base may be added dropwise to a mixture containing the compound of formula (5), the compound of formula (6), and the solvent in the reaction vessel. Another example is to add the compound of formula (6), the base, and the solvent to the reaction vessel, and then add the compound of formula (5) dropwise. Yet another example is to add the base and the solvent to the reaction vessel, and then add the compounds of formula (5) and (6) dropwise in sequence.

[0493] (Post-processing of IC; isolation and / or purification) The compound of formula (7), particularly compound (7-a), which is a product of step ic, can be used as a raw material for step ii. The compound of general formula (7) obtained in step ic may be isolated and / or purified and used in the next step, or it may be used in the next step without isolation. Whether or not to perform post-processing (isolation and / or purification) can be appropriately determined by a person skilled in the art, depending on the purpose and circumstances.

[0494] The compound of formula (7), particularly compound (7-a), which is the target product of step ic, can be isolated and purified from the reaction mixture by methods known to those skilled in the art (e.g., extraction, washing, crystallization including recrystallization, crystal washing and / or other operations), improved methods thereof, and any combination thereof.

[0495] Post-processing steps (isolation and / or purification) may include, but are not limited to, the following operations: extraction and washing operations, including separation of the organic layer from the aqueous layer, may be performed during post-processing. When separating the mixture into an organic layer and an aqueous layer, the mixture may be separated while still hot. For example, when separating the organic layer from the aqueous layer, a hot mixture may be used, or the mixture may be heated. Impurities may be removed by filtration operations, including thermal filtration.

[0496] In the washing procedure, if possible, the product dissolved or suspended in an organic solvent may be washed with water, warm water, an alkaline aqueous solution (e.g., a 5% to saturated sodium bicarbonate aqueous solution or a 1 to 10% sodium hydroxide aqueous solution) or an acidic aqueous solution (e.g., a 5 to 35% hydrochloric acid or a 5 to 35% sulfuric acid). These washing procedures may be combined.

[0497] When crystallizing the product, including recrystallization, and washing the crystals, refer to the explanation in step ii below.

[0498] In any of the above operations, the temperature can be appropriately adjusted by a person skilled in the art, depending on the purpose and circumstances.

[0499] In any post-processing operation and in operations where the product is used in subsequent steps, the amount of solvent can be appropriately adjusted by those skilled in the art by adding and removing it. Furthermore, solvent recovery and recycling may be performed as needed. For example, solvent used in the reaction may be recovered and recycled, and solvent used in post-processing (isolation and / or purification) may be recovered and recycled.

[0500] Post-processing (isolation and / or purification) can be performed by appropriately combining all or some of the above operations. Depending on the purpose, the above operations may be repeated. Furthermore, a person skilled in the art can appropriately select any combination and order of the above operations.

[0501] (Process ii (oxidation reaction)) Let's explain process ii.

[0502] Step II is an oxidation reaction. In step II, compound (8) is produced from compound (7) by oxidation. TIFF0007846022000039.tif64161(In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5 (This is as defined above.)

[0503] Examples of oxidation reactions in step ii include methods using oxidizing agents such as hydrogen peroxide, hypochlorite, and peroxides, as well as dimethyl sulfoxide oxidation such as ozone oxidation and Swan oxidation. Carrying out the reaction in step ii using sodium hypochlorite, potassium hypochlorite or other hypochlorites, sodium bisulfate, sodium persulfate (sodium peroxodisulfate), potassium persulfate, ammonium persulfate, potassium bisulfate (peroxides such as potassium peroxymonosulfate or Oxon®) instead of hydrogen peroxide is equivalent to the present invention and falls within the scope of the present invention.

[0504] Step ii is preferably a step of reacting the compound of formula (7) with hydrogen peroxide under specific conditions to produce the compound of formula (8);

[0505] [ka]

[0506] (In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5 (This is as defined above.)

[0507] (Raw material for step ii: compound of formula (7)) The compound of formula (7) is used as the raw material for step ii. The compound of formula (7) is a known compound or can be produced from a known compound according to a known method. For example, the preparation of the compound of formula (7) is described in WO2004 / 013106A1 (Patent Document 2), Reference Examples 1-1, 1-2 and 1-3, and WO2005 / 105755A1 (Patent Document 3), Examples 3-5 and WO2005 / 095352A1 (Patent Document 4), Examples 1-5. In addition, the compound of formula (7) can be prepared by similar methods. However, it is preferable that the compound of formula (7) is produced by the method of the present invention. That is, the compound of formula (7) is preferably produced by a method comprising steps ia, ib and ic as described herein.

[0508] (Product of step ii: compound of formula (8))

[0509] The product of step ii is the compound of formula (8), which corresponds to the compound of formula (7) used as a starting material.

[0510] In equations (7) and (8), R 1 , R 2 , R 3 , R 4 and R 5 This is as defined above. In equations (7) and (8), R 1 , R2 , R 3 , R 4 and R 5 Examples, preferred examples, more preferred examples, and particularly preferred examples are as described above. It was expected that the desired oxidation reaction would not proceed easily with the compounds of formula (7), especially with those having these preferred, more preferred, and particularly preferred substituents. However, contrary to expectations, it was found that the oxidation reaction proceeded sufficiently under the reaction conditions of the present invention.

[0511] [ka] (In equations (7), (8), and (9), R 1 , R 2 , R 3 , R 4 and R 5 (This is as defined above.) After oxidizing equation (7) to obtain equation (9), it is also possible to oxidize it to equation (8).

[0512] Particularly preferred specific examples of compounds of formula (8) are as follows:

[0513] [ka]

[0514] As mentioned above, in the method for producing the compound of formula (8) (SO2 derivative) from the compound of formula (7) (S derivative), it is desirable that the oxidation reaction proceeds sufficiently and that the proportion of the compound of formula (9) (SO derivative) in the product is sufficiently low. For example, in the reaction mixture after step ii, the proportion of the compound of formula (9) (SO derivative) is preferably 10% or less, more preferably 5% or less, more preferably 3% or less, more preferably 2% or less, and even more preferably 1% or less.

[0515] (Oxidizing agent in process ii) In the reaction of step ii, the aforementioned hypochlorite, alkali metal persulfate, ammonium persulfate, alkali metal persulfate, peroxide, etc., can be used as the oxidizing agent. In one embodiment, preferably, hydrogen peroxide, alkali metal persulfate, ammonium persulfate, alkali metal persulfate, more preferably, hydrogen peroxide, alkali metal persulfate, and even more preferably, hydrogen peroxide, sodium persulfate, sodium persulfate, potassium persulfate, ammonium persulfate, and potassium persulfate are used. In another embodiment, hydrogen peroxide is preferably used. In yet another embodiment, preferably, sodium persulfate, sodium persulfate, potassium persulfate, ammonium persulfate, potassium persulfate, and more preferably, potassium persulfate is used.

[0516] The form of hydrogen peroxide in step ii may be any form as long as the reaction proceeds. The form of hydrogen peroxide in step ii can be appropriately selected by those skilled in the art. However, considering safety, hazards, economic efficiency, etc., preferred forms of hydrogen peroxide include 10-70 wt% aqueous hydrogen peroxide solution, more preferably 20-70 wt% aqueous hydrogen peroxide solution, even more preferably 25-65 wt% aqueous hydrogen peroxide solution, even more preferably 30-65 wt% aqueous hydrogen peroxide solution, and particularly preferably 30-60 wt% aqueous hydrogen peroxide solution. Specific examples of hydrogen peroxide forms include, but are not limited to, 25 wt% aqueous hydrogen peroxide solution, 30 wt% aqueous hydrogen peroxide solution, 35 wt% aqueous hydrogen peroxide solution, 50 wt% aqueous hydrogen peroxide solution, 60 wt% aqueous hydrogen peroxide solution, etc. The range of hydrogen peroxide concentration may be any combination of the lower and upper limits of the above ranges, and any combination of the lower and upper limits of the above ranges is also within the scope of the present invention.

[0517] The amount of hydrogen peroxide used in step ii can be any amount as long as the reaction proceeds. The amount of hydrogen peroxide used in step ii can be adjusted as appropriate by those skilled in the art. However, from the viewpoint of yield, suppression of by-products, economic efficiency, and safety, the lower limit of the amount of hydrogen peroxide used is, for example, 2 moles or more, 2.3 moles or more, 2.5 moles or more, 2.8 moles or more, or 3 moles or more per mole of compound (raw material) of formula (7). The upper limit of the amount of hydrogen peroxide used is, for example, 10 moles or less, 8 moles or less, 7 moles or less, 6 moles or less, 5 moles or less, 4 moles or less, or 3 moles or less per mole of compound (raw material) of formula (7). The amount of hydrogen peroxide used is within any combination of the lower and upper limits of the above ranges. In one embodiment, the amount of hydrogen peroxide used in step ii is, for example, 2 moles or more, preferably 2 to 8 moles, more preferably 2 to 6 moles, even more preferably 2 to 5 moles, even more preferably 2 to 4 moles, even more preferably 2 to 3, and even more preferably 2.3 to 3 moles per mole of compound (raw material) of formula (7). In another embodiment, the amount of hydrogen peroxide used in step ii is, for example, 2 moles or more, preferably 2 to 10 moles, more preferably 3 to 6 moles, and even more preferably 3 to 5 moles per mole of compound (raw material) of formula (7).

[0518] Specific examples of alkali metal persulfates, ammonium persulfates, or alkali metal persulfates in step ii include, but are not limited to, sodium persulfate, potassium persulfate, or ammonium persulfate. Specific examples of hydrogen persulfates in step ii include, but are not limited to, sodium hydrogen persulfate or potassium hydrogen persulfate.

[0519] The amount of alkali metal persulfate, ammonium persulfate, or alkali metal hydrogen persulfate used in step ii may be any amount, as long as the reaction proceeds. The amount of alkali metal persulfate, ammonium persulfate, or alkali metal hydrogen persulfate used in step ii can be appropriately selected by a person skilled in the art. In one embodiment, the amount of alkali metal persulfate, ammonium persulfate, or alkali metal hydrogen persulfate used in step ii is, for example, 1.0 to 2.0 moles, preferably 1.0 to 1.5 moles, and more preferably 1.0 to 1.2 moles per mole of compound (raw material) of formula (7).

[0520] (Process ii; in the absence of transition metals) Oxidation reactions using hydrogen peroxide as the oxidizing agent in the presence of a transition metal catalyst have been reported. However, the method of the present invention does not require a transition metal catalyst. Therefore, the phrase "in the absence of a transition metal" means that no catalyst containing a transition metal catalyst is used. Accordingly, in this specification, "in the absence of a transition metal" may be optionally replaced with "in the absence of a transition metal catalyst." Examples of transition metals not used in step ii include, but are not limited to, tungsten, molybdenum, iron, manganese, vanadium, niobium, tantalum, titanium, zirconium, and copper. Examples of transition metal catalysts not used in step ii include, but are not limited to, tungsten catalysts (e.g., sodium tungstate dihydrate), molybdenum catalysts (e.g., ammonium molybdate tetrahydrate), iron catalysts (e.g., iron(III) acetylacetonate, iron(III) chloride), manganese catalysts (e.g., manganese(III) acetylacetonate), vanadium catalysts (e.g., vanadylacetylacetonate), niobium catalysts (e.g., sodium niobate), tantalum catalysts (e.g., lithium tantalate), titanium catalysts (e.g., titanium acetylacetonate, titanium tetrachloride), zirconium catalysts (e.g., zirconium chloride octahydrate), copper catalysts (e.g., copper(II) acetate, copper(I) bromide), etc.

[0521] (Acidic compound in step ii)

[0522] The reaction in step ii may be carried out in the presence of an acidic compound. From the viewpoint of yield, suppression of by-products, and economic efficiency, preferred examples of the acidic compound in step ii include, but are not limited to, mineral acids, carboxylic acids, sulfonic acids, phosphoric acids and mixtures thereof, more preferably mineral acids, carboxylic acids and mixtures thereof. The acidic compound may be a salt or acid anhydride thereof, as long as the reaction proceeds. This also includes those that form salts (e.g., sodium salts, potassium salts, etc.) and / or anhydrides of their acids (e.g., acetic anhydride, trifluoroacetic anhydride, etc.). In other words, as used herein, the term “acidic compound” includes their salts or acid anhydrides. A method of carrying out the reaction in step ii in the presence of a salt and / or acid anhydride of an acidic compound falls within the scope of the present invention as defined by the appended claims. As can be seen from Examples 2-29 below, for example, a method using a salt of sulfuric acid (e.g., alkali metal bisulfate salts such as sodium bisulfate and potassium bisulfate) as the acidic compound falls within the scope of the present invention. In addition, methods using alkali metal sulfates such as sodium sulfate and potassium sulfate are also equivalents of the present invention and fall within the scope of the present invention.

[0523] From the same viewpoint as above, preferred specific examples of the acidic compounds in step ii include, but are not limited to, the following: mineral acids (e.g., nitric acid, sulfuric acid, sodium bisulfate, potassium bisulfate, etc.), Carboxylic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, monochloroacetic acid, maleic acid, phthalic acid, benzoic acid, acetic anhydride, trifluoroacetic anhydride, etc.), Sulfonic acids (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), Phosphates (e.g., phosphoric acid, methyl phosphate, ethyl phosphate, phenyl phosphate, etc.), More preferably sulfuric acid, sodium bisulfate, potassium bisulfate, acetic acid, trifluoroacetic acid and mixtures thereof; even more preferably sulfuric acid, potassium bisulfate, acetic acid, trifluoroacetic acid and mixtures thereof; even more preferably sulfuric acid, acetic acid, trifluoroacetic acid and mixtures thereof.

[0524] The concentration of sulfuric acid can be appropriately selected by those skilled in the art. There are no particular restrictions on the concentration of sulfuric acid, but it is preferably 10% to 100%, more preferably 30% to 100%, and even more preferably 50% to 100%.

[0525] The acidic compound in step ii may be used alone or in any combination of two or more compounds in any proportion. The form of the acidic compound in step ii may be any form as long as the reaction proceeds. The form of the acidic compound can be appropriately selected by those skilled in the art. In addition, immobilized reagents and catalysts are generally known. These are reagents and catalysts immobilized on a support by adsorption or covalent bonding. Immobilized acidic compounds are not excluded from the scope of the present invention. On the other hand, from the standpoint of availability or reactivity, unimmobilized acidic compounds are preferred. The amount of acidic compound used in step ii may be any amount as long as the reaction proceeds. The amount of acidic compound used can be appropriately adjusted by those skilled in the art. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., the amount of acidic compound used is, for example, any combination of the lower and upper limits of the following ranges. In one embodiment, the amount of acidic compound used is, for example, greater than 0 (zero) moles per mole of compound (raw material) of formula (7), preferably 0.1 to 100 moles, more preferably 0.5 to 50 moles, even more preferably 1 to 40 moles, and even more preferably 2 to 30 moles. In another embodiment, the amount of the acidic compound used is, for example, greater than 0 moles per mole of the compound (raw material) of formula (7), preferably 1 to 100 moles, more preferably 1 to 50 moles, and even more preferably 1 to 30 moles. In yet another embodiment, for example, when the acidic compound is sulfuric acid, the amount of the acidic compound used is, for example, greater than 0 moles per mole of the compound (raw material) of formula (7), preferably 0.2 to 10 moles, more preferably 0.2 to 5 moles, and even more preferably 0.2 to 3 moles. In yet another embodiment, for example, when the acidic compound is sulfuric acid, the amount of the acidic compound used is, for example, 0.25 to 4 moles, 0.25 to 3.5 moles, preferably 0.3 to 3.5 moles, and 0.3 to 3 moles per mole of the compound (raw material) of formula (7). "When the acidic compound is sulfuric acid" refers to reactions using sulfuric acid, as shown in Examples 2-1 to 2-18.

[0526] Acidic compounds may also be used as solvents. In this case, the acidic compound contributes to the reaction itself and also functions as a solvent.

[0527] (Base in step ii)

[0528] The reaction in step ii may be carried out in the presence of a base. From the viewpoint of yield, suppression of by-products, and economic efficiency, preferred examples of the base in step ii include, but are not limited to, the following: carbonates, bicarbonates and mixtures thereof, preferably metal bicarbonates, metal carbonates and mixtures thereof, more preferably alkali metal bicarbonates, alkali metal carbonates and mixtures thereof, and even more preferably alkali metal carbonates. From a similar viewpoint as above, preferred specific examples of the base in step ii include, but are not limited to, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, more preferably sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, even more preferably potassium carbonate, potassium bicarbonate, sodium bicarbonate.

[0529] The base in step ii may be used alone or in any combination of two or more bases in any proportion. The form of the base in step ii may be any form as long as the reaction proceeds. The form of the base can be appropriately selected by those skilled in the art. In addition, immobilized reagents and catalysts are generally known. These are reagents and catalysts immobilized on a support by adsorption or covalent bonding. Immobilized bases are not excluded from the scope of the present invention. On the other hand, from the standpoint of availability or reactivity, unimmobilized bases are preferred. The amount of base used in step ii may be any amount as long as the reaction proceeds. From the viewpoint of yield, suppression of by-products, economic efficiency, etc., the amount of base used is, for example, any combination of the lower and upper limits of the following ranges. In one embodiment, the amount of base used is, for example, 0 to 2 moles, preferably 0.01 to 1 mole, more preferably 0.05 to 1 mole, and even more preferably 0.1 to 0.8 moles per mole of compound (starting material) of formula (7). In another embodiment, the amount of base used is, for example, 0.05 to 5 moles, preferably 0.1 to 3 moles, and more preferably 0.4 to 1.5 moles, per mole of compound (raw material) of formula (7). In yet another embodiment, the amount of base used is, for example, 0.4 to 0.6 moles, per mole of compound (raw material) of formula (7).

[0530] (Nitrile compound in step ii)

[0531] The reaction in step ii may be carried out in the presence of a nitrile compound. A nitrile compound is a compound having a nitrile group. Preferred examples of nitrile compounds in step ii include, but are not limited to, alkylnitrile derivatives, benzonitrile derivatives, and mixtures thereof. More preferably, alkylnitrile derivatives and mixtures thereof are included.

[0532] From the same viewpoint as above, specific examples of preferred nitrile compounds in step ii include, but are not limited to, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile, benzonitrile, p-nitrobenzonitrile, preferably acetonitrile, isobutyronitrile, succinonitrile, benzonitrile, p-nitrobenzonitrile, more preferably acetonitrile, isobutyronitrile, succinonitrile, and even more preferably acetonitrile.

[0533] The nitrile compounds in step ii may be used alone or in any combination of two or more compounds in any proportion. The amount of nitrile compounds used in step ii may be any amount as long as the reaction proceeds. The amount of nitrile compounds used can be adjusted as appropriate by those skilled in the art. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, the amount of nitrile compounds used should be greater than 0 moles, preferably 1 to 100 moles, more preferably 1 to 50 moles, and even more preferably 1 to 35 moles, per mole of compound (raw material) of formula (7). The nitrile compounds may also be used as a solvent. In this case, the nitrile compounds contribute to the reaction itself and also function as a solvent.

[0534] (Ketone compound in step ii)

[0535] The reaction in step ii may be carried out in or without the presence of a ketone compound. A ketone compound is a compound containing a ketone group. Whether or not to use a ketone compound can be appropriately determined by those skilled in the art. Examples of ketone compounds in step ii include, but are not limited to, 2,2,2-trifluoroacetophenone, methyl isobutyl ketone, or cyclohexanenone.

[0536] The ketone compounds in step ii may be used alone or in any combination of two or more compounds in any proportion. The amount of ketone compounds used in step ii may be any amount as long as the reaction proceeds. The amount of ketone compounds used can be adjusted as appropriate by those skilled in the art. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, the amount of ketone compounds used is, for example, 0.01 to 1.0 moles, preferably 0.05 to 0.8 moles, and more preferably 0.1 to 0.6 moles per mole of compound (starting material) of formula (7).

[0537] (Reaction solvent for step ii) From the viewpoint of ensuring the smooth progress of the reaction, it is preferable to carry out the reaction in step ii in the presence of a solvent. Any solvent may be used for the reaction in step ii, as long as the reaction proceeds.

[0538] Examples of solvents for the reaction in step ii include, but are not limited to, the following: aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, trichlorobenzene, nitrobenzene, etc.), halogenated aliphatic hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane (EDC), etc.), alcohols (e.g., methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol (tert-butanol is also called tert-butyl alcohol), pentanol, sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, hexanol, cyclohexanol, etc.), nitriles (e.g., acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile, benzonitrile, etc.), carboxylic acids (e.g., acetic acid, propionic acid, trifluoroacetic acid, trichloroacetic acid, etc.), and carboxylic acid esters (e.g., methyl acetate, ethyl acetate, propyl acetate). , isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, etc. ((In the present invention, "isomer of butyl acetate" is an equivalent of "butyl acetate," and "isomer of pentyl acetate" is an equivalent of "pentyl acetate."))), ethers (for example, tetrahydrofuran (THF), 1,4-dioxane, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), di Grimm (diglyme, etc.), ketones (e.g., acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone (MIPK), methyl isobutyl ketone (MIBK), etc.), amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), etc.), ureas (e.g., N,N'-dimethylimidazolidinone (DMI), tetramethylurea, etc.), sulfones (e.g., sulfolane, etc.), water, and any combination thereof in any proportion. "2-propanol" is also called "isopropyl alcohol" or "isopropanol".

[0539] A preferred example of the solvent for the reaction in step ii includes any combination of one or more (preferably one or two, more preferably one) organic solvents selected from alcohols, nitriles, carboxylic acids, and amides, and aqueous solvent in any proportion.

[0540] From the same viewpoint as above, preferred specific examples of the solvent for the reaction in step ii include any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, pentanol, sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile, benzonitrile, acetic acid, propionic acid, trifluoroacetic acid, N,N-dimethylformamide (DMF), and N,N-dimethylacetamide (DMAC) and aqueous solvent in any proportion.

[0541] From the same viewpoint as above, more preferred specific examples of the solvent for the reaction in step ii include any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methanol, ethanol, propanol, 2-propanol, butanol, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, succinonitrile, benzonitrile, acetic acid, propionic acid, trifluoroacetic acid, and N,N-dimethylformamide (DMF) and an aqueous solvent in any proportion.

[0542] From the same viewpoint as above, more preferred specific examples of the solvent for the reaction in step ii include any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methanol, ethanol, propanol, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, acetic acid, trifluoroacetic acid, and N,N-dimethylformamide (DMF) and an aqueous solvent in any proportion.

[0543] From the same viewpoint as above, particularly preferred specific examples of the solvent for the reaction in step ii include any combination of one or more (preferably one or two, more preferably one) organic solvents selected from methanol, acetonitrile, acetic acid, and N,N-dimethylformamide (DMF) and aqueous solvent in any proportion.

[0544] In either case, as long as the reaction proceeds, the solvent may be a single layer or separated into two layers. On the other hand, with respect to the reaction system of the invention, acetonitrile was predicted to be undesirable from the viewpoint of the affinity between the organic solvent and the aqueous solvent in the presence of the raw materials and / or intermediates (suggesting that the reaction may not proceed sufficiently). However, contrary to predictions, favorable results were obtained.

[0545] In step ii, the reaction using sulfuric acid as shown in Examples 2-1 to 2-18 includes, but is not limited to, the following organic solvents: Aromatic hydrocarbon derivatives (for example, benzene which may be substituted with 1 to 3 (preferably 1 or 2, more preferably 1) selected from (C1-C4) alkyl groups and chlorine atoms, specifically, for example, benzene, toluene, xylene, chlorobenzene, dichloronzene), Aliphatic halogenated hydrocarbons (for example, alkanes (C1-C4) which may be substituted with 1 to 10 chlorine atoms, specifically, for example, dichloromethane, 1,2-dichloroethane (EDC)), Nitriles (e.g., (C2-C5) alkanenitriles, specifically, acetonitrile), Carboxylic acid esters (for example, (C1-C4) alkyl(C1-C6) carboxylates, specifically, for example, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, hexyl acetate and its isomers. In the present invention, for example, "isomer of butyl acetate" is an equivalent of "butyl acetate"). Amides (for example, N,N-di((C1-C4)alkyl)(C1-C4)alkaneamides and 1-(C1-C4)alkyl-2-pyrrolidone, specifically, for example, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, N-methylpyrrolidone (NMP)), Urea compounds (e.g., N,N'-dimethylimidazolidinone (DMI), tetramethylurea), Sulfones (e.g., sulfolanes).

[0546] In one embodiment, they are preferably as follows: aromatic hydrocarbon derivatives, halogenated aliphatic hydrocarbons, nitriles, carboxylic acid esters, amides, More preferably, aromatic hydrocarbon derivatives, nitriles, carboxylic acid esters, and amides.

[0547] In another embodiment, they are preferably the following: benzene which may be substituted with 1 to 3 (preferably 1 or 2, more preferably 1) selected from (C1 to C4) alkyl groups and chlorine atoms, (C1 to C4) alkanes which may be substituted with 1 to 10 chlorine atoms, (C2-C5) alkanenitriles, (C1-C4) alkyl(C1-C6) carboxylates, N,N-di((C1-C4)alkyl)(C1-C4) alkaneamides and 1-(C1-C4) alkyl-2-pyrrolidone More preferably, benzene, (C2-C5)alkanenitrile, (C1-C4)alkyl(C1-C6)carboxylate, N,N-di((C1-C4)alkyl)(C1-C4)alkaneamide, and 1-(C1-C4)alkyl-2-pyrrolidone, which may be substituted with 1 to 3 (preferably 1 or 2, more preferably 1) atoms selected from (C1-C4)alkyl groups and chlorine atoms.

[0548] In yet another embodiment, they are preferably the following: benzene, toluene, xylene, chlorobenzene, dichlorolonzene, dichloromethane, 1,2-dichloroethane, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, hexyl acetate and its isomers, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, N-methylpyrrolidone (NMP), More preferably, toluene, xylene, chlorobenzene, dichlorolonzene, dichloromethane, 1,2-dichloroethane, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, hexyl acetate and its isomers, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, N-methylpyrrolidone (NMP), More preferably, toluene, xylene, chlorobenzene, dichloronzene, Acetonitrile, Methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, hexyl acetate and its isomers, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, N-methylpyrrolidone (NMP) More preferably, toluene, xylene, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and its isomers, pentyl acetate and its isomers, hexyl acetate and its isomers, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, N-methylpyrrolidone (NMP).

[0549] In step ii, the reaction using sulfuric acid as shown in Examples 2-1 to 2-18 is undesirable in the presence of (C1-C6) alcohols, particularly (C1-C4) alcohols. This reaction is preferably carried out in the absence of (C1-C6) alcohols, particularly (C1-C4).

[0550] (C1-C6) alcohols mean (C1-C6) alkyl-OH (where the (C1-C6) alkyl portion has the same meaning as defined above). Examples of (C1-C4) alcohols include, but are not limited to, methanol, ethanol, propanol (i.e., 1-propanol), 2-propanol, butanol (i.e., 1-butanol), sec-butanol, isobutanol, tert-butanol, pentanol (i.e., 1-pentanol), sec-amyl alcohol, 3-pentanol, 2-methyl-1-butanol, isoamyl alcohol, tert-amyl alcohol, hexanol (i.e., 1-hexanol), cyclohexanol, etc.

[0551] (C1-C4) alcohols mean (C1-C4) alkyl-OH (where the (C1-C4) alkyl portion has the same meaning as defined above). Examples of (C1-C4) alcohols include, but are not limited to, methanol, ethanol, propanol (i.e., 1-propanol), 2-propanol, butanol, sec-butanol, isobutanol, tert-butanol, etc.

[0552] In yet another embodiment, in step ii, the reaction using sulfuric acid as shown in Examples 2-1 to 2-18, in one embodiment, the example of the organic solvent includes an organic solvent having 1 to 25, preferably 2 to 25, more preferably 2 to 20, and even more preferably 2 to 19 acceptors. In another embodiment, the example of the organic solvent includes an organic solvent having 5 to 25, preferably 5 to 20, more preferably 7 to 20, and even more preferably 8 to 19 acceptors.

[0553] In yet another embodiment, in step ii, the reaction using sulfuric acid as shown in Examples 2-1 to 2-18, the example of the organic solvent includes an organic solvent having a dielectric constant of 1 to 70, preferably 1 to 40, more preferably 2 to 40, and even more preferably 2 to 38.

[0554] In yet another embodiment, in step ii, the reaction using sulfuric acid as shown in Examples 2-1 to 2-18, the examples of organic solvents include organic solvents having Rohrschneider polarity parameters 1 to 7, preferably 2 to 7.

[0555] (Number of acceptors) In this specification, for the purpose of determining the acceptor number, for example, one can refer to the following document: Christian Reichardt, "Solvents and Solvent Effects in Organic Chemistry", 3rd, updated and enlarged edition, WILEY-VCH, 2003, pp. 25-26. The definition of the acceptor number using 31P-NMR chemical shift values ​​is described in the aforementioned document and is incorporated herein by reference. Examples of solvents having specified values ​​are described in the aforementioned document and are incorporated herein by reference.

[0556] (Relative permittivity) In this specification, with respect to relative permittivity (also commonly known as "dielectric constant"), for example, the following references can be consulted: The Chemical Society of Japan, ed., "Chemical Handbook (Basic Edition)", Maruzen Co., Ltd., 5th revised edition, 2004, pp. I-770-777. A. Maryott and Edgar R. Smith, National Bureau of Standards Circular 514, Table of Dielectric Constants of Pure Liquids, United States Department of Commerce, National Bureau of Standards, August 10, 1951. These are incorporated into the present invention by reference. Examples of solvents having the specified values ​​are described in the aforementioned references and are incorporated into the present invention by reference.

[0557] (Rohrschneider polarity parameter) For Rohrschneider's polarity parameters, see, for example, the following website: https: / / www.shodex.com / ja / dc / 06 / 0117.html. These are incorporated by reference into the present invention. Examples of solvents having the specified values ​​are described in the aforementioned document and are incorporated by reference into the present invention.

[0558] The "solvent of the reaction" includes all organic solvents and aqueous solvents used in the reaction. The "solvent of the reaction" does not include organic solvents and aqueous solvents used in post-reaction workup (e.g., isolation, purification, etc.). The "organic solvents" used in the reaction include organic solvents in the starting material solution and the reactant solution. The "aqueous solvents" used in the reaction include water in the starting material solution and the reactant solution (e.g., water in the hydrogen peroxide solution).

[0559] The amounts of organic solvent and aqueous solvent used in the reaction of step ii are not particularly limited, as long as the reaction system can be sufficiently stirred. The amounts and ratios of organic solvent and aqueous solvent used are, for example, within any combination of the lower and upper limits of their ranges as described herein.

[0560] However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the amount of organic solvent used in the reaction of step ii is, for example, 0 to 3 L, preferably 0 to 2 L, more preferably 0.4 to 1.8 L, per mole of compound (starting material) of formula (7). However, it is not limited to these. In another embodiment, the amount of organic solvent used in the reaction of step ii is, for example, 0.1 to 5 L, preferably 0.1 to 3 L, per mole of compound (starting material) of formula (7). However, it is not limited to these.

[0561] From the same viewpoint as above, in one embodiment, the amount of aqueous solvent used in step ii is, for example, preferably 0.01 to 2 L (liters), more preferably 0.05 to 1 L, even more preferably 0.1 to 0.5 L, and even more preferably 0.1 to 0.3 L. However, it is not limited to these amounts.

[0562] When using a combination of two or more organic solvents, the proportions of the two or more organic solvents may be any proportion, as long as the reaction proceeds. When using a combination of an organic solvent and water, the proportions of the organic solvent and water may be any proportion, as long as the reaction proceeds. However, in each method of the oxidation reaction of the present invention, preferred organic solvents and their preferred amounts, preferred amounts of water, and their ratios have been found. These are as described herein.

[0563] (Reaction temperature in process ii) The reaction temperature of step ii is not particularly limited. However, from the viewpoint of yield, suppression of by-products, economic efficiency, etc., it is within any combination of the following lower and upper limits. In one embodiment, the reaction temperature of step ii is, for example, 0°C to 100°C, preferably 30°C to 100°C, more preferably 30°C to 80°C, even more preferably 40°C to 80°C, and still more preferably 40°C to 60°C. In another embodiment, the reaction temperature of step ii is, for example, 40°C to 100°C, preferably 45°C to 100°C, and still more preferably 45°C to 80°C. In yet another embodiment, the reaction temperature of step ii is, for example, 0°C to 80°C, preferably 5°C to 60°C, more preferably 5°C to 50°C, even more preferably 5°C to 40°C, and still more preferably 10°C to 40°C.

[0564] In yet another embodiment, in step ii, the reaction using sulfuric acid as shown in Examples 2-1 to 2-18 is performed at 30°C to 100°C, preferably 35°C to 90°C, more preferably 40°C to 80°C, and in yet another embodiment, the reaction using sulfuric acid is performed at 35°C to 100°C, 35°C to 110°C, 35°C to 120°C, 35°C to 150°C, 40°C to 150°C, 60°C to 150°C, and 70°C to 150°C.

[0565] (Reaction time for process ii) The reaction time in step ii is not particularly limited. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, in one embodiment, the reaction time in step ii is, for example, 5 minutes to 48 hours, preferably 10 minutes to 24 hours, and more preferably 10 minutes to 12 hours. In another embodiment, the reaction time in step ii is, for example, 1 hour to 48 hours, preferably 1 hour to 24 hours, and more preferably 30 minutes to 12 hours. However, the reaction time can be appropriately adjusted by those skilled in the art.

[0566] (Preparation method for process ii) There are no particular restrictions on the order in which the raw materials, oxidizing agent, acidic compound, base, solvent, etc., are added. As long as the reaction proceeds, the order in which they are added does not matter.

[0567] (Preparation method for step ii; method using a base) As long as the reaction proceeds, in the method using a base in step ii, the order in which the starting materials, base, and oxidizing agent are added does not matter. However, from the viewpoint of yield, etc., "adding all at once" or "adding the base and oxidizing agent simultaneously" is preferred. From the viewpoint of yield, suppression of by-products, economic efficiency, safety, etc., "adding the base and oxidizing agent simultaneously" is more preferred. In "adding the base and oxidizing agent simultaneously," the compound of formula (7) as a starting material is charged before the start of "adding the base and oxidizing agent simultaneously." However, in this case, some of the compound of formula (7) as a starting material may be charged during "adding the base and oxidizing agent simultaneously."

[0568] (Addition rate of base in step ii) In the "simultaneous addition of base and oxidizing agent," from the viewpoint of yield, suppression of by-products, economic efficiency, and safety, the rate of base addition in step ii is, for example, within any combination of the lower and upper limits of the following ranges: The rate of base addition in step ii is, for example, 0.01 mol / hour to 1 mol / hour, preferably 0.01 mol / hour to 0.7 mol / hour, more preferably 0.01 mol / hour to 0.6 mol / hour, even more preferably 0.01 mol / hour to 0.5 mol / hour, even more preferably 0.02 mol / hour to 0.5 mol / hour, and even more preferably 0.03 mol / hour to 0.5 mol / hour per mole of compound of formula (7).

[0569] (Addition rate of the oxidizing agent in step ii) In the "simultaneous addition of base and oxidizing agent," the rate of addition of the oxidizing agent in step ii is, for example, any combination of the lower and upper limits of the following ranges, from the viewpoint of yield, suppression of by-products, economic efficiency, and safety. In one embodiment, the rate of addition of the oxidizing agent in step ii is, for example, 0.06 moles / hour to 2 moles / hour, preferably 0.1 moles / hour to 1.5 moles / hour, and more preferably 0.13 moles / hour to 1 mole / hour, per mole of compound (7). In another embodiment, the rate of addition of the oxidizing agent in step ii is, for example, 0.05 moles / hour to 6 moles / hour, preferably 0.05 moles / hour to 5 moles / hour, more preferably 0.1 moles / hour to 5 moles / hour, and even more preferably 0.2 moles / hour to 5 moles / hour, per mole of compound (7).

[0570] (Relationship between the addition rates of the base and oxidizing agent in step ii) In the "simultaneous addition of base and oxidizing agent," from the viewpoint of yield, suppression of by-products, economic efficiency, and safety, it is preferable that the rate of base addition in step ii is the same as the rate of oxidizing agent addition in step ii, or that the rate of oxidizing agent addition in step ii is faster than the rate of base addition in step ii, and more preferably that the rate of oxidizing agent addition in step ii is faster than the rate of base addition in step ii. For example, the rate of oxidizing agent addition in step ii is 1 to 30 times (preferably more than 1 and up to 30 times), 1 to 20 times (preferably more than 1 and up to 20 times), or 1 to 10 times (preferably more than 1 and up to 10 times) the rate of base addition in step ii.

[0571] (Addition time of base and oxidizing agent in step ii, and maturation time) In the "simultaneous addition of base and oxidizing agent," from the viewpoint of yield, suppression of by-products, economic efficiency, and safety, the addition time of the base and oxidizing agent in step ii is preferably 0.5 hours or more, more preferably 0.75 hours or more, and even more preferably 1 hour or more. The addition time of the base in step ii is, for example, 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 12 hours. From the same viewpoint as above, the addition time of the oxidizing agent in step ii is, for example, 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 12 hours. From the same viewpoint as above, the maturation time after addition in step ii is, for example, 0.1 to 24 hours, preferably 0.1 to 12 hours, more preferably 0.2 to 9 hours, and even more preferably 0.5 to 6 hours.

[0572] (Addition time, maturation time, reaction time) In this specification, “maturation time” refers to the stirring time after the addition of the raw materials and / or reactants (e.g., hydrogen peroxide, acidic compounds, bases) is complete. If the method of adding the raw materials and reactants is “bulk addition”, then “reaction time” is “maturation time”. When raw materials and / or reactants are added over a certain period of time, the "addition time" is the time from the start of adding the raw materials and / or reactants such as hydrogen peroxide and bases until the entire amount has been added. In this case as well, the "maturation time" is the stirring time after the addition of the raw materials and / or reactants is complete. In this case, it is presumed that the reaction begins after the addition starts, and the "reaction time" is the sum of the "addition time" and the "maturation time".

[0573] (Preparation method for step ii; method using both acidic compounds and bases) Furthermore, the oxidation reaction in step ii can be carried out using acidic compounds and bases. In one embodiment, the compound of formula (7) can be reacted with an oxidizing agent under acidic conditions, and then reacted with an oxidizing agent under neutral to alkaline conditions to produce the compound of formula (8). In another embodiment, the compound of formula (7) can be reacted with an oxidizing agent in the presence of an acidic compound, and then reacted with an oxidizing agent under neutral to alkaline conditions to produce the compound of formula (8). In yet another embodiment, the compound of formula (7) can be reacted with an oxidizing agent in the presence of an acidic compound, and then the compound of formula (8) can be produced by reacting the oxidizing agent with a base. In this specification, the phrase "in the presence of an acidic compound" may be optionally replaced with the phrase "under acidic conditions." The phrase "under neutral to alkaline conditions" may be optionally replaced with the phrase "using a base."

[0574] In one embodiment, the acidic conditions when using the above-mentioned acidic compound are, for example, a pH value of 6.0 or less, preferably greater than 0 and 5.5 or less, more preferably greater than 0 and 5.0 or less, even more preferably greater than 0 and 4.0 or less, and even more preferably greater than 0 and 3.0 or less. In another embodiment, for example, a pH value of 6.0 or less, preferably greater than -1 and 5.5 or less, more preferably greater than -1 and 5.0 or less, even more preferably greater than -1 and 4.0 or less, and even more preferably greater than -1 and 3.0 or less.

[0575] In one embodiment, the neutral to alkaline conditions described above include, for example, a pH value of 6.0 or higher, preferably in the range of 6.5 to 14.0, more preferably 7.0 to 12.0, and even more preferably 8.0 to 10.0. In another embodiment, for example, a pH value of 7.0 or higher, preferably in the range of 7.5 to 14.0, more preferably 8.0 to 12.0, and even more preferably 8.5 to 10.0.

[0576] (Embodiment of the reaction) This reaction can be carried out in a batch manner using a reaction vessel, or in a flow reaction using a continuous reactor. A continuous reactor is a reactor that allows for the continuous supply of raw materials and the simultaneous progress of the reaction. One example of a continuous reactor is a flow reactor. A flow reactor is a reactor that can continuously supply raw materials and carry out the reaction continuously. Flow reactors are broadly classified into tubular flow reactors (including tube-type flow reactors) and tank-type flow reactors, both of which can carry out the reaction continuously. The flow reactor of the present invention may be provided with temperature control means for controlling the temperature of the flow reactor, for example, a temperature control unit for heating or cooling may be provided. The temperature control unit may be any appropriate type, and examples of temperature control units include baths and jackets. The style of the bath and jacket may be any appropriate style. Furthermore, there are no particular restrictions on the material of the flow reactor, as long as it is not affected by the raw materials or solvent. Examples include metals (e.g., titanium, nickel, stainless steel, Hastelloy C), resins (e.g., fluororesin), glass, and porcelain (e.g., ceramics).

[0577] The continuous reaction of the present invention does not preclude implementation in a tank-type flow reactor. However, a preferred flow reactor is, for example, a tubular flow reactor. The tubular flow reactor of the present invention only needs to be capable of continuously flowing a liquid or gas-liquid mixture, and the cross-sectional shape of the tube may be circular, square, polygonal, elliptical, or any combination of these shapes. Furthermore, there are no particular restrictions on the material of the tube as long as it is not affected by the raw materials and solvents, and examples include metals (e.g., titanium, nickel, stainless steel, Hastelloy C), resins (e.g., fluororesin), glass, porcelain (e.g., ceramics), etc., but fluororesin (e.g., Teflon®) is preferred. The tubular flow reactor of the present invention may also be provided with temperature control means for controlling the temperature, for example, a temperature control unit for heating or cooling may be provided. The temperature control unit may be any appropriate type, and examples of temperature control units include baths and jackets. The style of the bath and jacket may be any appropriate style. Such flow-type reactors can include, for example, spiral-type, shell-and-tube-type, and plate heat exchange-type reactors.

[0578] There are no particular restrictions on the arrangement of the tubes in the tubular flow reactor of the present invention; for example, they may be arranged in a straight line, a curved line, or a coil. A preferred arrangement is, for example, a tubular reactor in which the tubes are arranged in a coil. In addition, there may be one tube, or two or more tubes may be bundled together regularly or irregularly at appropriate intervals. For convenience, this specification will be based on a tubular flow reactor having one tube, but if it is desired to increase production efficiency, a tubular flow reactor in which two or more tubes are bundled together regularly or irregularly at appropriate intervals may be used as described herein. Furthermore, the tubular flow reactor of the present invention may optionally include a mixer. The mixer is not particularly limited as long as it has the function of continuously mixing two or more fluids, such as gas and liquid or liquid and liquid. Examples include Y-shaped mixers, T-shaped mixers, pipeline-type mixers (line mixers including static mixers, etc.). A line mixer including a static mixer, etc., may also be a tubular flow reactor.

[0579] (A reaction in the flow of the market) When a flow-through reaction is adopted, a predetermined mixture of compound (7), an acidic compound (or base), hydrogen peroxide, and a solvent (further additions may be made if necessary) is passed through a tubular reactor to react. In this case, it is preferable to use a tubular reactor equipped with a heating device and to pass the mixture through a reaction tube heated to a predetermined temperature. The reaction temperature is not particularly limited. However, from the viewpoint of yield, suppression of by-products, and economic efficiency, a range of 0°C to 120°C, preferably 30°C to 100°C, can be exemplified.

[0580] The equivalent diameter of the tube in the tubular reactor of the present invention is not particularly limited as long as it is large enough for a liquid or gas-liquid mixture to flow continuously, but it is preferable to be 0.5 mm or larger from the viewpoint of production efficiency. Examples of preferred equivalent diameters include 0.5 mm to 50 mm, preferably 0.5 mm to 30 mm. In this invention, "equivalent diameter (De)" is a value defined by the following formula. De = 4·Af / Wp (In the formula, Af represents the cross-sectional area of ​​the channel, and Wp represents the length of the wetted edge.) For example, the equivalent diameter of a circular tube with radius r is: De = 4·πr 2 / 2πr = 2r

[0581] The length of the tube in the tubular flow reactor of the present invention is not particularly limited, as long as it is within a range in which the raw material compounds can be heated and reacted sufficiently. For example, it is 1 m or more, preferably in the range of 5 m to 80 m. In order to carry out the method of the present invention efficiently, it is necessary to react at a predetermined temperature and / or for sufficient reaction time, so a length of 5 m or more is generally preferred, but it is not limited to this.

[0582] The flow rate in the flow reactor of the present invention, preferably a tubular flow reactor, is usually 0.01 mL / min or more, preferably 0.05 mL / min or more, although this also depends on the equivalent diameter of the tube.

[0583] The pressure inside the tubular flow reactor is, for example, 0.1 MPa to 10 MPa, preferably 0.3 MPa to 5 MPa, but is not limited to these values.

[0584] (Post-processing of step ii; isolation and purification) The compound of formula (8), particularly pyroxasulfone (8-a), which is the target product of step ii, can be isolated and purified from the reaction mixture by methods known to those skilled in the art (e.g., extraction, washing, crystallization including recrystallization, crystal washing and / or other operations) and improved methods thereof, and any combination thereof.

[0585] In step ii, as shown in the examples, it is preferable to decompose unreacted peroxides such as hydrogen peroxide by treating the reaction mixture with a reducing agent (for example, an aqueous solution of sodium sulfite) after the reaction.

[0586] Post-processing steps (isolation and / or purification) may include, but are not limited to, the following operations: extraction and / or washing operations, including separation of the organic layer from the aqueous layer; when separating the mixture into an organic layer and an aqueous layer, the mixture may be separated while still hot; for example, when separating the organic layer from the aqueous layer, a hot mixture may be used, or the mixture may be heated; impurities may be removed by filtration operations, including thermal filtration.

[0587] Post-processing may include crystallization of the target product, including recrystallization, and washing of the crystals. Crystallization of the target product, including recrystallization, may be carried out by conventional methods known to those skilled in the art. For example, a poor solvent may be added to a solution of the target product in a good solvent. Another example is that a saturated solution of the target product may be cooled.

[0588] As yet another example, the solvent may be removed from the organic solvent solution of the target product (including the reaction mixture). In this case, examples of usable organic solvents include the water-miscible organic solvents described below, preferred examples, more preferred examples, and even more preferred examples. Water may be added to the system beforehand, and then the organic solvent may be removed. In this case, the organic solvent may be removed by azeotropy with water. The removal of the organic solvent may be carried out under heating, reduced pressure, and atmospheric pressure. As yet another example, water may be added to the water-miscible organic solvent solution of the target product. Examples of water-miscible organic solvents include, but are not limited to, alcohols (e.g., methanol, ethanol, 2-propanol, butanol, t-butanol), nitriles (e.g., acetonitrile), ethers (e.g., tetrahydrofuran (THF), 1,4-dioxane), ketones (e.g., acetone), amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), etc.), sulfoxides (e.g., dimethyl sulfoxide (DMSO), etc.), and combinations thereof, preferably methanol, ethanol, 2-propanol, butanol, acetonitrile, acetone, and combinations thereof, more preferably ethanol, 2-propanol, butanolacetonitrile, and combinations thereof. "Water-miscible organic solvent" is synonymous with "water-soluble organic solvent." "2-propanol" is also called "isopropyl alcohol" or "isopropanol."

[0589] In any of the above cases, a seed crystal may be used.

[0590] The crystal washing operation may involve washing the filtered crystals with a solvent. Alternatively, the crystal suspension (slurry) may be stirred and then filtered. In either case, examples of usable solvents include the aforementioned water-miscible organic solvents, preferred examples, more preferred examples, even more preferred examples, and water.

[0591] In all of the above cases (crystallization operations including recrystallization, crystal washing operations, etc.), the amount of solvent such as a water-miscible organic solvent and the amount of water may be in any ratio as long as the objective is achieved. When using a combination of a water-miscible organic solvent and water, the ratio of these may be in any ratio as long as the objective is achieved. When using a combination of two or more water-miscible organic solvents, the ratio of these may be in any ratio as long as the objective is achieved. The amounts and ratios can be appropriately adjusted by a person skilled in the art depending on the purpose and circumstances.

[0592] In any of the above operations (extraction, washing, crystallization including recrystallization, crystal washing, etc.), the temperature can be appropriately adjusted by those skilled in the art. However, from the viewpoint of yield, purity, and economic efficiency, for example, the temperature is 0°C to 100°C, preferably 5°C to 90°C, and more preferably 10°C to 80°C. Heating and cooling should be performed within these temperature ranges.

[0593] In any of the above operations (extraction, washing, crystallization including recrystallization, crystal washing, etc.), the amount of organic solvent (including water-miscible organic solvents) and / or water can be appropriately adjusted by those skilled in the art by adding and removing them. Furthermore, solvent recovery and recycling may be performed as needed. For example, solvents used in the reaction may be recovered and recycled, and solvents used in post-treatment (isolation and / or purification) may be recovered and recycled.

[0594] Post-processing (isolation and / or purification) can be performed by appropriately combining all or some of the above operations. Depending on the circumstances, the above operations may be repeated to suit the purpose of isolation and / or purification. Furthermore, a person skilled in the art can appropriately select any combination and order of the above operations.

[0595] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way by these examples.

[0596] In this specification, the following equipment and conditions were used to measure the physical properties and yields of the examples, comparative examples, and reference examples. In addition, the products obtained in this invention are known compounds and were identified by conventional methods known to those skilled in the art.

[0597] (Measurement of pH) Equipment: A glass electrode type hydrogen ion concentration indicator, such as the HM-20P manufactured by Toa DKK Corporation or a similar model. (HPLC analysis: High-performance liquid chromatography analysis) (HPLC analysis conditions) Equipment: Shimadzu Corporation LC2010 series or equivalent. Column: YMC-Pack, ODS-A, A-312 (150mm x 6.0mm ID, S-5μm, 120A) Eluent:

[0598] [Table 1]

[0599] Flow rate: 1.0 ml / min Detection: UV 230nm Column temperature: 40℃ Injection volume: 5 μL

[0600] For HPLC analysis methods, please refer to the following literature as needed. Reference (a): The Chemical Society of Japan (ed.), "New Experimental Chemistry Course 9: Analytical Chemistry II", pp. 86-112 (1977), published by Shingo Iizumi, Maruzen Co., Ltd. Reference (b): The Chemical Society of Japan (ed.), "Experimental Chemistry Course 20-1 Analytical Chemistry," 5th edition, pp. 130-151 (2007), Publisher: Seishiro Murata, Maruzen Co., Ltd.

[0601] (Yield and purity) Unless otherwise specified, the yield in this invention can be calculated from the number of moles of the target compound obtained relative to the number of moles of the raw material compound (starting compound). In other words, the term "yield" means "molar yield." Therefore, the yield is expressed by the following formula: Yield (%) = (moles of target compound obtained) / (moles of starting compound) × 100

[0602] However, for example, in evaluating the reaction yield of the target substance, the yield of impurities, and the purity of the product, HPLC area percentage analysis or GC area percentage analysis may be used.

[0603] In this specification, room temperature and ambient temperature are defined as temperatures between 10°C and 30°C. In this specification, "RT", "rt", "rt", and "rt" mean room temperature.

[0604] In this specification, the term "overnight" means between 8 and 16 hours.

[0605] In this specification, the operation of “age / aged / aging” includes stirring the mixture by a conventional method known to those skilled in the art.

[0606] In the examples herein, unless otherwise specified, “sulfuric acid” means concentrated sulfuric acid. Examples of concentrated sulfuric acid include, but are not limited to, 98% sulfuric acid. [Examples]

[0607] [Example 1] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole (compound 7-a)

[0608] [Example 1-1] (Process pre-ia) Preparation of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole (compound 1-a)

[0609] [ka]

[0610] 5-Difluoromethoxy-4-hydroxymethyl-1-methyl-3-trifluoromethylpyrazole (46.7 g, purity: 68.6%, containing acetonitrile, 0.13 mol, 100 mol%) was mixed with thionyl chloride (17.0 g, 0.14 mol, 110 mol%) dropwise over 1 hour at an internal temperature of 20°C to 30°C. After the addition, the mixture was aged for 1 hour at an internal temperature of 20°C to 30°C. After the reaction was complete, nitrogen was blown into the reaction mixture for 30 minutes to remove excess thionyl chloride, and ethyl acetate (78 mL, 0.6 L / mol) was added. The resulting ethyl acetate solution of the title compound (1-a) was 134 g.

[0611] [Examples 1-2] (process ia) Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole (compound 7-a)

[0612] [ka]

[0613] An ethyl acetate solution (134 g, equivalent to 0.13 mol) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-pyrazole (1-a), prepared in step pre-ia, was cooled to below 10°C under ice-coloured stirring. An aqueous solution (134.6 g, purity: 27%, equivalent to 0.14 mol) of [5,5-dimethyl(4,5-dihydroisoxazolo-3-yl)]thiocarboxamidine hydrobromide (2-b) was added to this solution, and then a 48% sodium hydroxide aqueous solution (54.2 g, 0.65 mol, 500 mol%) was added dropwise over 30 minutes, ensuring that the internal temperature did not exceed 10°C. After the dropwise addition, the mixture was aged at below 10°C for 30 minutes, then heated to 25°C and aged for 4 hours. After the reaction was complete, the reaction mixture was separated into an organic layer and an aqueous layer. The obtained organic layer was analyzed by HPLC absolute calibration curve, and the yield of the target product (7-a) was 91.6% (127.8 g, throughout the two steps).

[0614] [Examples 1-3] (Process pre-ib) Preparation of 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole (compound 4-a)

[0615] [ka]

[0616] 1.7 g (10.00 mmol, 100 mol%) of 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (MTP) and 1.6 g (40.00 mmol, 400 mol%) of sodium hydroxide were dissolved in 10 ml of water. While stirring this solution at room temperature, 1.7 g (20 mmol) of 35% formaldehyde aqueous solution (35% formalin solution) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. To this, 10 ml of water solution of 2.1 g (10.00 mmol) of [5,5-dimethyl(4,5-dihydroisoxazolo-3-yl)]thiocarboxamidine hydrochloride (ITCA / HCl,2-a) was added dropwise at room temperature, and the mixture was stirred for 2 hours. After the reaction, 5.0 g (50 mmol) of 35% hydrochloric acid was added dropwise. The precipitated crystals were filtered by suction and washed twice with 5 mL of water. By drying in a hot air dryer, 2.5 g of compound (4-a) was obtained as pale yellow crystals. The yield was 80.1%.

[0617] [Examples 1-4] (Process ib) Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole (compound 7-a)

[0618] [ka]

[0619] To 100 ml of acetonitrile, 33.2 g (93.3% purity, 0.1 mol) of 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole synthesized in Examples 1-4 and 12.0 g (0.3 mol) of 99% sodium hydroxide were added and the mixture was stirred at room temperature for 1 hour. This suspension was cooled on ice and, while maintaining a temperature range of 5-15°C, 17.3 g (0.2 mol) of chlorodifluoromethane was introduced over 4 hours, and the mixture was reacted within the same temperature range for 5 hours. After the reaction was complete, 100 ml of toluene, 50 ml of water, and 10 ml of 35% hydrochloric acid were added, and the organic layer was separated. The aqueous layer was re-extracted with 50 ml of toluene, and the combined organic layers were sequentially washed with 50 ml of water and 20 ml of saturated brine. The obtained organic layers were dried over sodium sulfate, and the solvent was removed by distillation to obtain 38.0 g of compound (7-a) with a purity of 85%. The yield was 90%.

[0620] [Examples 1-5] (Process pre-ic) Preparation of (5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)isothiourea hydrobromide (compound 5-b)

[0621] [ka]

[0622] To 30 mL of an ethanol solution of 4-bromomethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-pyrazole (1-b; purity 75.0%, 46.3 mmol), 3.5 g (46.3 mmol) of thiourea was added, and the mixture was heated under reflux and stirred for 1 hour. The solvent was removed by distillation under reduced pressure, and the mixture was washed with a mixed solvent of ethyl acetate and n-hexane to obtain 13.8 g of the target product (5-b) as white crystals. The yield was 77.5%.

[0623] (process ic) Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole (compound 7-a)

[0624] [ka]

[0625] To 10 mL of an ethanol solution of (5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)isothiourea hydrobromide (1.93 g, 5.00 mmol), 0.48 g (12.00 mmol) of sodium hydroxide and 10 mL of water were added and the mixture was stirred at room temperature for 30 minutes. Then, 0.67 g (5.00 mmol) of 3-chloro-5,5-dimethyl-2-isoxazoline was added at room temperature and the mixture was stirred under reflux for 12 hours. After confirming the completion of the reaction, the solvent was removed by distillation under reduced pressure. The resulting residue was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.02 g of the target product (7-a). The yield was 56.7%. [Reference example 1] Preparation of an aqueous solution of [5,5-dimethyl(4,5-dihydroisoxazolo-3-yl)]thiocarboxamidine hydrobromide

[0626] [ka]

[0627] A butyl acetate solution (251.5 g, purity: 18%, 0.25 mol) of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (BIO) obtained by the method described in WO2006 / 038657A was mixed with thiourea (20 g, 0.26 mol, 105 mol%), and the internal temperature was raised to 15°C to 25°C. 35% hydrochloric acid (26 g, 0.25 mol, 100 mol%) was added dropwise over 30 minutes at an internal temperature of 15°C to 25°C. After the addition, the mixture was aged at an internal temperature of 15°C to 25°C for 6 hours. After the reaction was complete, water (88 g, 0.35 L / mol) was added and stirred for 15 minutes, separating the reaction mixture into an organic layer and an aqueous layer. Water (25 g, 0.1 L / mol) was added to the resulting organic layer and stirred for 15 minutes, separating the reaction mixture into an organic layer and an aqueous layer. When the resulting aqueous layers were combined, 208.6 g of an aqueous solution containing the target product with a yield equivalent to 90% was obtained. The obtained target product contains hydrobromide salt derived from the raw material BIO and hydrochloride salt derived from hydrochloric acid.

[0628] [Example 2-1] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0629] [ka]

[0630] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 2.94 g (1.5 L / mol) of acetonitrile, sulfuric acid (0.77 g, 7.50 mmol, 300 mol%), and 35% aqueous hydrogen peroxide solution (0.81 g, 7.12 mmol, 285 mol%, containing 0.57 g (0.2 L / mol) of water) were added to a reaction flask, stirred at 75°C, and aged for 6 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 86% yield.

[0631] [Examples 2-2 to 2-6 and Comparative Examples 1 to 3] The reaction and analysis were carried out in the same manner as in Example 2-1, except that the amount of acetonitrile solvent, the amount of sulfuric acid, the reaction temperature, and the aging time were changed as shown in Table 2. The results are shown in Table 2. In addition, the results of Example 2-1 are also summarized in Table 2.

[0632] [Table 2]

[0633] [Examples 2-7] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0634] The reaction equation is the same as in Example 2-1.

[0635] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 2.94 g of toluene (1.5 L / mol), sulfuric acid (0.77 g, 7.50 mmol, 300 mol%), and a 30% aqueous hydrogen peroxide solution (0.81 g, 7.12 mmol, 285 mol%, containing 0.57 g of water (0.2 L / mol)) were added to a reaction flask, stirred at 75°C, and aged for 15 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 91% yield.

[0636] [Examples 2-8 to 2-18 and Comparative Examples 4 to 7] The reaction and analysis were carried out in the same manner as in Example 2-7, except that the organic solvent and its amount, the amount of sulfuric acid, the reaction temperature, and the maturation time were changed as shown in Table 3. The results are shown in Table 3. In addition, the results of Example 2-7 are also summarized in Table 3.

[0637] [Table 3]

[0638] In the sulfuric acid-based method shown in Examples 2-1 to 2-18, (C1-C4) alcohol solvents, which were presumed to be preferable based on prior art, were found to be unfavorable, contrary to expectations. On the other hand, generally, when the reaction system separates into two layers, a decrease in reactivity is expected. However, even when using non-polar solvents such as toluene, which were expected to separate from the hydrogen peroxide aqueous solution, the reaction proceeded sufficiently in this sulfuric acid-based method. Aromatic hydrocarbon derivatives such as toluene are inexpensive, easily recyclable, and contribute to sustainability. A wide range of organic solvents other than alcohols can be used in this method, and it was found that this method is versatile for solvents other than alcohols. That is, in one embodiment, this reaction using sulfuric acid can be carried out in the presence of organic solvents having a dielectric constant of 1 to 40, excluding alcohols. In another embodiment, this reaction can be carried out in the presence of organic solvents having an acceptor number of 5 to 25 and a dielectric constant of 1 to 40. In yet another embodiment, this reaction can be carried out in the presence of organic solvents having a Rohrschneider polarity parameter of 1 to 7, excluding alcohols. In yet another embodiment, this reaction can be carried out in the presence of an organic solvent having an acceptor number of 5 to 25 and a Rohrschneider polarity parameter of 1 to 7. For the acceptor number, see, for example, the following reference: Christian Reichardt, "Solvents and Solvent Effects in Organic Chemistry", 3rd, updated and enlarged edition, WILEY-VCH, 2003, pp. 25-26. For the relative permittivity (also commonly known as "dielectric constant"), see, for example, the following reference: The Chemical Society of Japan (ed.), "Chemical Handbook (Basic Edition)", Maruzen Co., Ltd., 5th revised edition, 2004, pp. I-770-777. For the Rohrschneider polarity parameter, see, for example, the following website.https: / / www.shodex.com / ja / dc / 06 / 0117.html.

[0639] [Examples 2-19] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0640] The reaction equation is the same as in Example 2-1.

[0641] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 2.94 g (1.5 L / mol) of acetonitrile, trifluoroacetic acid (0.86 g, 7.50 mmol, 300 mol%), and a 30% aqueous hydrogen peroxide solution (0.81 g, 7.12 mmol, 285 mol%, containing 0.57 g (0.2 L / mol) of water) were added to a reaction flask, stirred at 75°C, and aged for 6 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 89% yield.

[0642] [Examples 2-20] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0643] The reaction equation is the same as in Example 2-1.

[0644] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 2.97 g of methanol (1.5 L / mol), trifluoroacetic acid (0.86 g, 7.50 mmol, 300 mol%), and a 30% aqueous hydrogen peroxide solution (0.81 g, 7.12 mmol, 285 mol%, containing 0.57 g of water (0.2 L / mol)) were added to a reaction flask, stirred at 75°C, and aged for 6 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0.8% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 90% yield.

[0645] [Examples 2-22] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0646] The reaction equation is the same as in Example 2-1.

[0647] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 3.93 g of acetic acid (1.5 L / mol), sulfuric acid (0.25 g, 2.5 mmol, 100 mol%), and 35% aqueous hydrogen peroxide solution (0.69 g, 7.12 mmol, 285 mol%, containing 0.45 g of water (0.18 L / mol)) were added to a reaction flask, stirred at 75°C, and aged for 48 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 2.4% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 88.7% yield.

[0648] [Examples 2-23 to 2-28] The reaction and analysis were carried out in the same manner as in Example 2-22, except that the acid, acid equivalents, reaction temperature, and maturation time were changed as shown in Table 4. The results are shown in Table 4. In addition, the results of Example 2-22 are also summarized in Table 4.

[0649] [Table 4]

[0650] [Examples 2-29] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0651] The reaction equation is the same as in Example 2-1.

[0652] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 2.94 g (1.5 L / mol) of acetonitrile, potassium bisulfate (1.02 g, 7.50 mmol, 300 mol%), and 30% aqueous hydrogen peroxide solution (0.81 g, 7.12 mmol, 285 mol%, containing 0.57 g (0.2 L / mol) of water) were added to a reaction flask, and the mixture was stirred at 75°C and aged for 48 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 1.3% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 88% yield.

[0653] As can be seen from the above examples, the acidic compound, particularly sulfuric acid, may be a salt. A method of carrying out the reaction in step ii in the presence of a salt of sulfuric acid is within the scope of the present invention.

[0654] [Examples 2-30] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0655] The reaction equation is the same as in Example 2-1.

[0656] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 0.99 g of acetonitrile (0.5 L / mol), acetic acid (2.25 g, 37.5 mmol, 1500 mol%, 0.86 L / mol), and 35% aqueous hydrogen peroxide solution (0.69 g, 7.12 mmol, 285 mol%, containing 0.45 g of water (0.18 L / mol)) were added to a reaction flask, stirred at 50°C, and aged for 24 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 3.38% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 90% yield.

[0657] [Examples 2-31] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0658] The reaction equation is the same as in Example 2-1.

[0659] 8.98 g of compound (7-a), purity: 100%, 25.0 mmol, 100 mol%, 29.6 g of acetonitrile (1.5 L / mol), sulfuric acid (7.51 g, 75.0 mmol, 300 mol%), and a 35% hydrogen peroxide aqueous solution (6.92 g, 71.3 mmol, 285 mol%, containing 4.50 g of water (0.18 L / mol)) were mixed in an ice bath in a flask. The entire mixture was filled into a syringe and transferred at a rate of 0.2 mL / min using a syringe pump. The transferred mixture passed through a 15 m long Teflon tube with an inner diameter of 2.4 mm, submerged in an 80°C oil bath, and was collected in another flask. When the reaction mixture was sampled and analyzed two hours after the start of distribution, the reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was found to be present at 0.57% (HPLC area percentage; 230 nm). The target substance (8-a) was present at 90% (HPLC area percentage; 230 nm). Further analysis of the reaction solution after continuing the flow for 4 hours revealed that the reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm). The target substance (8-a) was present at 95% (HPLC area percentage; 230 nm).

[0660] [Examples 2-32] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0661] The reaction equation is the same as in Example 2-1.

[0662] Compound (7-a) (3.59 g, purity: 100%, 10.0 mmol, 100 mol%), 7.88 g (1.0 L / mol) of acetonitrile, trifluoroacetic acid (3.42 g, 30.0 mmol, 300 mol%), and a 35% aqueous hydrogen peroxide solution (2.77 g, 28.5 mmol, 285 mol%, containing 1.80 g (0.18 L / mol) of water) were mixed in a flask at room temperature. The mixture was transferred at 0.1 mL / min using a plunger pump. The transferred mixture passed through a tube with an inner diameter of 4 mm and a length of 3.6 mm, which was submerged in a 90°C water bath, and was collected in another flask. When the reaction mixture was sampled and analyzed two hours after the start of distribution, the reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was found to be 0% (HPLC area percentage; 230 nm). The target substance (8-a) was present at 91% (HPLC area percentage; 230 nm).

[0663] [Example 3-1] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0664] The reaction equation is the same as in Example 2-1.

[0665] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 3.14 g (1.6 L / mol) of acetonitrile, and 35% aqueous hydrogen peroxide solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g (0.3 L / mol) of water) were added to a reaction flask and stirred at room temperature. Then, 0.6 M potassium carbonate was added. 2 ml of um aqueous solution (0.8 L / mol, 48 mol%) was added, and the mixture was aged at room temperature for 30 minutes. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 88% yield.

[0666] [Example 3-2] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0667] The reaction equation is the same as in Example 2-1.

[0668] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 4.0 g of benzonitrile (1.6 L / mol), and 35% hydrogen peroxide aqueous solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g of water (0.3 L / mol)) were added to a reaction flask and stirred at room temperature. Then, 2 ml of 0.6 M potassium carbonate aqueous solution (0.8 L / mol, 48 mol%) was added and the mixture was aged at room temperature for 17 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC yielded the target product (8-a) in 87.0% yield (HPLC area percentage; 230 nm).

[0669] [Example 3-3] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0670] The reaction equation is the same as in Example 2-1.

[0671] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 3.08 g of isobutyronitrile (1.6 L / mol), and a 35% aqueous hydrogen peroxide solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g of water (0.3 L / mol)) were added to a reaction flask and stirred at room temperature. Then, 2 ml of 0.6 M aqueous potassium carbonate solution (0.8 L / mol, 48 mol%) was added and the mixture was aged at room temperature for 16 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC yielded the target product (8-a) in a yield of 95.6% (HPLC area percentage; 230 nm).

[0672] [Examples 3-4] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0673] The reaction equation is the same as in Example 2-1.

[0674] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 3.78 g (1.6 L / mol) of dimethylformamide, 0.50 g (12.5 mmol, 250 mol%), and 35% aqueous hydrogen peroxide solution (1.22 g (12.5 mmol, 500 mol%) containing 0.79 g (0.3 L / mol) of water) were added to a reaction flask and stirred at room temperature. Then, 2 ml (0.8 L / mol, 48 mol%) of 0.6 M aqueous potassium carbonate solution was added and the mixture was aged at room temperature for 18 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0.9% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC yielded the target product (8-a) in a yield of 89.7% (HPLC area percentage; 230 nm).

[0675] [Examples 3-5] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0676] The reaction equation is the same as in Example 2-1.

[0677] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 3.78 g (1.6 L / mol) of dimethylformamide, 1.85 g (12.5 mmol, 500 mol%), and 35% aqueous hydrogen peroxide solution (1.22 g (12.5 mmol, 500 mol%) containing 0.79 g (0.3 L / mol) of water) were added to a reaction flask and stirred at room temperature. Then, 2 ml (0.8 L / mol, 48 mol%) of 0.6 M aqueous potassium carbonate solution was added and the mixture was aged at room temperature for 30 minutes. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0.3% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC yielded the target product (8-a) in a yield of 87.2% (HPLC area percentage; 230 nm).

[0678] [Examples 3-6] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0679] The reaction equation is the same as in Example 2-1.

[0680] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 3.14 g of acetonitrile (1.6 L / mol), and a 35% aqueous hydrogen peroxide solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g of water (0.3 L / mol)) were added to a reaction flask and stirred at room temperature. 6 ml of 0.6 M aqueous potassium bicarbonate solution (2.4 L / mol, 144 mol%) was added and the mixture was aged for 18 hours. The pH at this time was 8.25. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 94% yield.

[0681] [Examples 3-7] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0682] The reaction equation is the same as in Example 2-1.

[0683] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 3.14 g of acetonitrile (1.6 L / mol), and a 35% aqueous hydrogen peroxide solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g of water (0.3 L / mol)) were added to a reaction flask and stirred at room temperature. Then, 2 ml of 0.6 M aqueous sodium carbonate solution (0.8 L / mol, 48 mol%) was added and the mixture was allowed to mature for 2 hours. The pH at this time was 7.85. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 89% yield.

[0684] [Examples 3-8] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0685] The reaction equation is the same as in Example 2-1.

[0686] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 3.14 g of acetonitrile (1.6 L / mol), and a 35% aqueous hydrogen peroxide solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g of water (0.3 L / mol)) were added to a reaction flask and stirred at room temperature. 6 ml of 0.6 M aqueous sodium bicarbonate solution (2.4 L / mol, 144 mol%) was added, and the mixture was aged for 18 hours. The pH at this time was 7.98. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 96% yield.

[0687] [Examples 3-9] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0688] The reaction equation is the same as in Example 2-1.

[0689] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%) was dissolved in 3.14 g (1.6 L / mol) of acetonitrile in a reaction flask and stirred at a temperature of 50-60°C. Then, 2 ml (0.8 L / mol, 48 mol%) of 0.6 M potassium carbonate aqueous solution and 35% hydrogen peroxide aqueous solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g (0.3 L / mol) of water) were added dropwise simultaneously over 5 hours, and the mixture was stirred at 60°C and aged for 1 hour. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 0.39% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 82% yield.

[0690] [Examples 3-10 to 3-16] The reaction and analysis were carried out in the same manner as in Example 3-9, except that the amount of hydrogen peroxide, the time of hydrogen peroxide addition, the base, the amount of base, the reaction temperature, and the maturation time were changed as shown in Table 5. The reaction temperature refers to the addition temperature and the maturation temperature. The results are shown in Table 5. In addition, the results of Example 3-9 are also summarized in Table 5. In Examples 3-9 to 3-10, the rate of base addition to hydrogen peroxide was 0.1 moles / hour or 0.5 moles / hour per mole of compound (7). In Examples 3-9 to 3-10, the hydrogen peroxide addition rate was 1 mole / hour or 5 moles / hour per mole of compound (7).

[0691] [Table 5]

[0692] [Example 4] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0693] The reaction equation is the same as in Example 2-1.

[0694] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 2.94 g (1.5 L / mol) of acetonitrile, sulfuric acid (0.023 g, 0.225 mmol, 9 mol%), and a 30% aqueous hydrogen peroxide solution (0.81 g, 7.12 mmol, 285 mol%, containing 0.57 g (0.2 L / mol) of water) were added to a reaction flask, stirred at 75°C, and aged for 6 hours. The reaction mixture was then cooled to room temperature, at which point its pH was -0.05.

[0695] The reaction mixture was stirred at room temperature and then 30% hydrogen peroxide solution (0.61 g, 5.37 mmol, 215 mol%, containing 0.43 g of water (0.17 L / mol)) and 0.6 M potassium carbonate solution (3.0 g, 1.80 mmol, 72 mol%) were added. The mixture was stirred at room temperature and allowed to mature for 0.5 hours. The pH at this time was 9.31. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 1.51% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in 80% yield.

[0696] [Example 5-1] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0697] The reaction equation is the same as in Example 2-1.

[0698] Compound (7-a) (0.45 g, purity: 100%, 1.25 mmol, 100 mol%), 0.83 g of acetonitrile (0.85 L / mol), 3.19 g of water (2.55 L / mol), and 45% potassium persulfate (1.88 g, 1.38 mmol, 110 mol%) were added to a reaction flask, and the mixture was stirred at 80°C and aged for 3 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 3.12% (HPLC area percentage; 230 nm) at this point. The target substance (8-a) was 95.7% at this point (HPLC area percentage; 230 nm).

[0699] [Example 5-2] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0700] The reaction equation is the same as in Example 2-1.

[0701] Compound (7-a) (0.45 g, purity: 100%, 1.25 mmol, 100 mol%), 0.83 g of acetonitrile (0.85 L / mol), 3.19 g of water (2.55 L / mol), 45% potassium persulfate (1.88 g, 1.38 mmol, 110 mol%), and cyclohexanone (0.04 g, 0.25 mmol, 20 mol%) were added to a reaction flask, and the mixture was stirred at 80°C and aged for 3 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 4.13% (HPLC area percentage; 230 nm) at this point. The target substance (8-a) was 94.4% at this point (HPLC area percentage; 230 nm).

[0702] [Reference example 2] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0703] The reaction equation is the same as in Example 2-1.

[0704] Method described in Example 4 of CN111574511A (Patent Document 10).

[0705] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 2.97 g of methanol (1.5 L / mol), sulfuric acid (0.023 g, 0.225 mmol, 9 mol%), and a 30% aqueous hydrogen peroxide solution (0.81 g, 7.12 mmol, 285 mol%, containing 0.57 g of water (0.2 L / mol)) were added to a reaction flask, stirred at room temperature, and aged for 6 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 13.97% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method showed that the target product (8-a) was not obtained in 0% yield. This method is not reproducible.

[0706] [Reference example 3] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0707] The reaction was carried out in the same manner as described in CN111574511A (Patent Document 10), Example 4, except that the reaction temperature was changed to heated conditions.

[0708] The reaction equation is the same as in Example 2-1.

[0709] Under a nitrogen atmosphere, compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 2.97 g of methanol (1.5 L / mol), sulfuric acid (0.023 g, 0.225 mmol, 9 mol%), and a 30% aqueous hydrogen peroxide solution (0.81 g, 7.12 mmol, 285 mol%, containing 0.57 g of water (0.2 L / mol)) were added to a reaction flask, stirred at 66°C, and aged for 6 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 93.8% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. Analysis by HPLC external standard method yielded the target product (8-a) in a yield of 4.4%. The yield was extremely low.

[0710] [Comparative Example 9] (Investigation of acidic compounds) Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0711] The reaction equation is the same as in Example 2-1.

[0712] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 2.94 g (1.5 L / mol) of acetonitrile, 0.92 g (7.50 mmol, 300 mol%), and 35% aqueous hydrogen peroxide solution (0.69 g (7.12 mmol, 285 mol%) containing 0.45 g (0.18 L / mol) of water) were added to a reaction flask, stirred at 75°C, and aged for 24 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 80.92% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. HPLC analysis (area percentage, 230 nm) revealed that the target product (8-a) was present in a 17% concentration.

[0713] [Comparative Examples 10-16] (Investigation of acidic compounds) The reaction and analysis were carried out in the same manner as in Comparative Example 9, except that the acid, acid equivalents, reaction temperature, and maturation time were changed as shown in Table 6. The results are shown in Table 6. In addition, the results of Comparative Example 9 are also summarized in Table 6.

[0714] [Table 6]

[0715] [Comparative Example 17] The reaction was carried out in the same manner as in Example 5-1, except that approximately three times the amount of potassium persulfate was initially used. Contrary to expectations, the yield was low. Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0716] Compound (7-a) (0.45 g, purity: 100%, 1.25 mmol, 100 mol%), 0.83 g of acetonitrile (0.85 L / mol), 3.19 g of water (2.55 L / mol), and 45% potassium persulfate (5.12 g, 3.75 mmol, 300 mol%) were added to a reaction flask, stirred at 80°C, and aged for 6 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 31.47% (HPLC area percentage; 230 nm) at this point. The target substance (8-a) was present at 61.98% (HPLC area percentage; 230 nm) at this point.

[0717] [Comparative Example 18] The reaction was carried out in the same manner as in Example 5-2, except that approximately three times the amount of potassium persulfate was initially used. Contrary to expectations, the yield was low. Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0718] The reaction equation is the same as in Example 2-1.

[0719] Compound (7-a) (0.45 g, purity: 100%, 1.25 mmol, 100 mol%), 0.83 g of acetonitrile (0.85 L / mol), 3.19 g of water (2.55 L / mol), 45% potassium persulfate (5.12 g, 3.75 mmol, 300 mol%), and cyclohexanone (0.04 g, 0.25 mmol, 20 mol%) were added to a reaction flask, and the mixture was stirred at 80°C and aged for 7 hours. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 29.6% (HPLC area percentage; 230 nm) at this point. The target substance (8-a) was present at 69.6% (HPLC area percentage; 230 nm) at this point.

[0720] [Comparative Examples 19-22] (Solvent study when using potassium persulfate) The reaction was carried out in the same manner as in Example 5-1, except for the solvent, reaction temperature, and aging time. Contrary to expectations, the yield was low for all solvents. The results are shown in Table 7.

[0721] [Table 7]

[0722] [Comparative Example 23] (Consideration of bases) Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0723] The reaction equation is the same as in Example 2-1.

[0724] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%), 3.14 g (1.6 L / mol) of acetonitrile, and 35% aqueous hydrogen peroxide solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g (0.3 L / mol) of water) were added to a reaction flask and stirred at room temperature. 6 ml (2.4 L / mol) of 0.6 M aqueous sodium acetate solution was then added and the mixture was aged for 18 hours. The pH at this time was 6.70. The reaction intermediate, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfinyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 9-a; SO derivative), was present at 3.7% (HPLC area percentage; 230 nm) at this point. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. HPLC analysis (area percentage, 230 nm) revealed that the target product (8-a) was present at 20%.

[0725] [Comparative Examples 24-31] (Investigation of bases and investigation of solvents in the presence of bases) The reaction and analysis were carried out in the same manner as in Comparative Example 23, except that the solvent, amount of solvent, base, equivalent amount of base, reaction temperature, and maturation time were changed as shown in Table 8. The results are shown in Table 8. In addition, the results of Comparative Example 23 are also summarized in Table 8.

[0726] [Table 8]

[0727] [Comparative Example 32] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0728] The reaction equation is the same as in Example 2-1.

[0729] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%) was dissolved in 3.14 g (1.6 L / mol) of acetonitrile in a reaction flask and stirred at a temperature of 50-60°C. 2 ml (0.8 L / mol, 48 mol%) of 0.6 M potassium carbonate aqueous solution and 35% hydrogen peroxide aqueous solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g (0.3 L / mol) of water) were added dropwise over 30 minutes, and the mixture was then aged at 60°C for 2 hours. The raw material (compound 7-a) was present at 9.6% (HPLC area percentage; 230 nm), and the reaction intermediate (compound 9-a; SO derivative) was present at 0.6% (HPLC area percentage; 230 nm). The target substance (8-a) was present at 84.7% (HPLC area percentage; 230 nm). When the addition time was short, the yield was relatively low.

[0730] [Comparative Example 33] Preparation of 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole (compound 8-a)

[0731] The reaction equation is the same as in Example 2-1.

[0732] Compound (7-a) (0.90 g, purity: 100%, 2.5 mmol, 100 mol%) was dissolved in 3.14 g (1.6 L / mol) of acetonitrile, and 2 ml (0.8 L / mol, 48 mol%) of 0.6 M potassium carbonate aqueous solution was added. The mixture was stirred at a temperature of 50-60°C. A 35% hydrogen peroxide aqueous solution (1.22 g, 12.5 mmol, 500 mol%, containing 0.79 g (0.3 L / mol) of water) was added dropwise over 30 minutes, and the mixture was then aged at 60°C for 2 hours. The raw material (compound 7-a) was present at 82.0% (HPLC area percentage; 230 nm), and the reaction intermediate (compound 9-a; SO derivative) was present at 3.8% (HPLC area percentage; 230 nm). The target substance (8-a) was present at 11.1% (HPLC area percentage; 230 nm). When hydrogen peroxide was added first, and then only the base was added dropwise, the yield was even lower.

[0733] [Comparative Example 34] Preparation of 3-[(1,3,5-trimethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0734] [ka]

[0735] The compound (0.21 g, purity: 100%, 0.83 mmol, 100 mol%), 0.98 g of acetonitrile (1.5 L / mol), sulfuric acid (0.25 g, 2.50 mmol, 300 mol%), and a 30% aqueous hydrogen peroxide solution (0.27 g, 2.37 mmol, 285 mol%, containing 0.19 g of water (0.22 L / mol)) were added to a reaction flask, stirred at 75°C, and aged for 6 hours. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. HPLC analysis (area percentage, 230 nm) revealed that the target product was present in a 0.5% concentration.

[0736] [Comparative Examples 35-37] The reaction and analysis were carried out in the same manner as in Comparative Example 34, except that the substituents, solvent, and acid of the raw materials were changed as shown in Table 9. The results are shown in Table 9.

[0737] [ka] (R 3A This is as shown in Table 9.

[0738] [Table 9]

[0739] [Comparative Example 38] (Step iii) Preparation of 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazole-4-yl)methylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole

[0740] [ka]

[0741] The compound (0.26 g, purity: 100%, 0.83 mmol, 100 mol%), 1.05 g (1.6 L / mol) of acetonitrile, and 35% aqueous hydrogen peroxide solution (0.41 g, 14.17 mmol, 500 mol%, containing 0.28 g (0.34 L / mol) of water) were added to a reaction flask and stirred at room temperature. Then, 0.67 ml (0.8 L / mol) of 0.6 M aqueous potassium carbonate solution was added and the mixture was allowed to mature for 30 minutes. Acetonitrile was added to the reaction mixture, and the reaction mixture was dissolved in a homogeneous solution. The target product was present at 0% (HPLC area percentage; 230 nm) at this point.

[0742] [Comparative Example 39] The reaction and analysis were carried out in the same manner as in Comparative Example 36, except that the substituents of the raw materials were changed as shown in Table 10. The results are shown in Table 10. In addition, the results for Comparative Example 36 are also summarized in Table 10.

[0743] [ka] (R 3A (This is as shown in Table 10.)

[0744] [Table 10]

[0745] All publications, patents, and patent applications described herein are incorporated herein in their entirety by reference for the purpose of describing and disclosing the methods described herein, which may be used in connection with the description herein. All publications, patents, and patent applications described herein are expressly incorporated herein by reference to the extent necessary to understand or complete the disclosure of the present invention, to the same extent as if each were incorporated individually. All publications, patents, and patent applications discussed above and throughout this specification are provided solely for disclosure prior to the filing date of this application.

[0746] Any method or reagent similar to or equivalent to those described herein may be used in the methods and practices of the present invention. Therefore, the present invention is not limited by the foregoing description, but is intended to be defined by the claims and their equivalents. These equivalents fall within the scope of the present invention as defined by the appended claims. [Industrial applicability]

[0747] As disclosed in Patent Document 1, compounds of general formula (8) (sulfone derivatives: SO2 derivatives) have excellent herbicidal activity. The present invention provides a novel industrially preferred method for producing compounds of general formula (8) that are useful as herbicides.

[0748] As described above in this specification, the method of the present invention is economical, environmentally friendly, and has high industrial value. In particular, the method of the present invention has a sufficiently low proportion of the compound of formula (9) (sulfoxide derivative: SO derivative) in the product. Here, the compound of formula (9) (sulfoxide derivative: SO derivative) is an intermediate in the oxidation reaction and can cause a decrease in the quality of the herbicide and phytotoxicity to crops. In addition, the present invention provides a reproducible and implementable method. Therefore, the present invention has high industrial applicability.

Claims

1. A method for producing the compound of formula (8), comprising the following step ii: (Step ii) In the absence of transition metals, in the presence of a base and an organic solvent, the compound of formula (7) is reacted with an oxidizing agent at 10°C to 40°C to produce the compound of formula (8), where the base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, the organic solvent is acetonitrile, propionitrile, butyronitrile, isobutyronitrile or benzonitrile, and the amount of organic solvent is 1 to 3 liters per mole of the compound of formula (7); (In equations (7) and (8), R １ It is methyl, R ２ It is trifluoromethyl, R ３ It is difluoromethyl, R ４ and R ５ (It is methyl.)

2. A method for producing the compound of formula (8), comprising the following step ii: (Step ii) In the absence of transition metals, in the presence of a base and an organic solvent, the compound of formula (7) is reacted with an oxidizing agent at 40°C to 80°C to produce the compound of formula (8), where the base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, the organic solvent is acetonitrile, propionitrile, butyronitrile, isobutyronitrile or benzonitrile, the base and oxidizing agent are added simultaneously, and the addition time is 1 hour or more; (In equations (7) and (8), R １ It is methyl, R ２ It is trifluoromethyl, R ３ It is difluoromethyl, R ４ and R ５ is methyl.)

3. A method according to claim 1 or 2, wherein the organic solvent is acetonitrile, isobutyronitrile, or benzonitrile.

4. A method according to claim 1 or 2, wherein the organic solvent is acetonitrile.

5. A method for producing the compound of formula (8), comprising the following step ii: (Step ii) In the absence of transition metals, in the presence of a base, a nitrile compound, and an organic solvent, the compound of formula (7) is reacted with an oxidizing agent to produce the compound of formula (8), where the base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate, the nitrile compound is succinonitrile or p-nitrobenzonitrile, and the organic solvent is an amide; (In equations (7) and (8), R １ It is methyl, R ２ It is trifluoromethyl, R ３ It is difluoromethyl, R ４ and R ５ (It is methyl.)

6. A method according to claim 5, wherein the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone.

7. A method according to claim 5, wherein the organic solvent is N,N-dimethylformamide.

8. A method according to any one of claims 1 to 7, wherein the oxidizing agent in step ii is hydrogen peroxide.

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