Method for preparing monosulfoxide derivatives

Abstract

The present invention provides a method for manufacturing monosulfoxide.

Description

Technology Field

[0001] The present invention relates to a method for manufacturing monosulfoxide derivatives. Background Technology

[0002] Sulfoxide derivatives are attracting attention in fields such as pesticides (Patent Document 1). Therefore, it is important to produce sulfoxide derivatives selectively and in high yield. As a method for producing sulfoxide derivatives, the oxidation of sulfide derivatives is known. However, conventional oxidation of sulfide derivatives had the following drawbacks or problems.

[0003] Examples 13 and 27 of Patent Document 1 disclose that sulfoxide derivatives can be produced by an oxidation reaction with metachloroperbenzoic acid. However, considering environmental aspects, the use of metachloroperbenzoic acid is undesirable for industrial production. The reasons are as follows. After the reaction, metachloroperbenzoic acid becomes metachlorobenzoic acid that becomes waste. Consequently, the use of metachloroperbenzoic acid places a heavy burden on the environment. Furthermore, since metachloroperbenzoic acid is expensive, the method of using metachloroperbenzoic acid is not industrially desirable.

[0004] Meanwhile, oxidation using hydrogen peroxide is an industrially desirable and useful method. The reasons are as follows. Hydrogen peroxide is environmentally friendly because it turns into harmless water after the reaction. In addition, hydrogen peroxide is industrially inexpensive.

[0005] Patent Documents 2 and 3 disclose that sulfoxide derivatives can be produced by an oxidation reaction with hydrogen peroxide using a catalyst that essentially requires a ligand. However, ligands are difficult to obtain industrially, so they must be prepared in advance. Furthermore, the catalyst must be adjusted from the metal compound and the ligand before the reaction begins, and the use of ligands is not industrially desirable in terms of the difficulty and / or cost of industrial production. In addition, cumbersome operations were required to remove the used ligands. Moreover, the method described in Patent Document 2 uses benzoic acid derivatives. From the above perspective, the use of benzoic acid derivatives is also not industrially desirable.

[0006] Furthermore, for example, in the method described in Patent Document 2, it was found that a cumbersome operation to remove the metal used as a catalyst was also required. Prior art literature

[0007] Patent Document 1: International Publication No. 2013 / 157229 Patent Document 2: International Publication No. 2017 / 150478 Patent Document 3: US2011 / 0015405A1 (Japanese Patent Application No. 2012-532906) The problem to be solved

[0008] There was an urgent need for a method for manufacturing sulfoxide derivatives that can solve one or more defects or problems in the aforementioned prior art.

[0009] Accordingly, the objective of the present invention is to provide a method for manufacturing sulfoxide derivatives that is industrially desirable, economical, and environmentally friendly. In other words, it was desired to provide a method that is inexpensive and can reduce the environmental burden.

[0010] For example, one of the specific objectives of the present invention is to produce sulfoxide derivatives using hydrogen peroxide, which is attracting attention as a clean and excellent oxidizing agent, without using metachloroperbenzoic acid as an oxidizing agent.

[0011] Another specific objective of the present invention is to provide a simple and inexpensive manufacturing method that does not use ligands and benzoic acid derivatives. It also avoids the cumbersome task of removing ligands and benzoic acid.

[0012] Another specific objective of the present invention is to avoid the cumbersome operation of removing the metal used as a catalyst.

[0013] In addition, the following problem was identified in the examination of oxidation reactions that do not use ligands, etc. The sulfide derivative of formula (A) below has a structural feature in that it has two sulfide sites that are oxidized in the oxidation reaction. It is necessary to selectively oxidize only one of the sulfide sites and not oxidize the other sulfide site, thereby selectively producing a monosulfoxide derivative.

[0014] The details are as follows. In the oxidation reaction of the sulfide derivative of Formula (A) below, there is a possibility that a desired compound and an undesirable compound may be formed due to two reaction sites. The desired product is the monosulfoxide derivative of Formula (B) below, while the disulfoxide derivative of Formula (C) below is unnecessary. The disulfoxide derivative of Formula (C), which is an unnecessary byproduct, reduces the yield of the target monosulfoxide derivative of Formula (B). Furthermore, because the physical properties of both derivatives are similar, it is difficult to obtain the purified target monosulfoxide derivative of Formula (B) in industrial production by removing the byproduct disulfoxide derivative of Formula (C) from the crude product after the oxidation reaction. In other words, it is difficult to separate and purify the target product with a high yield on an industrial scale. Therefore, it was desired to be able to selectively produce the desired monosulfoxide derivative of formula (B) by avoiding non-selective oxidation (i.e., over-oxidation) to the disulfoxide derivative of formula (C).

[0015] [Chemical Formula 1]

[0016]

[0017] In short, another specific objective of the present invention is to provide a method for selectively and in high yield producing only a desired monosulfoxide derivative from a sulfide derivative having a structural feature of having two oxidizable sulfide sites. To achieve this objective, it is necessary to provide a selective oxidation reaction that avoids excessive oxidation. means of solving the problem

[0018] In light of the above circumstances, the inventors have diligently researched methods for manufacturing sulfoxide derivatives. As a result, the inventors unexpectedly discovered that the above problem can be solved by providing the following method for manufacturing the compound of formula (B). Based on this finding, the inventors have completed the present invention.

[0019] That is, the present invention is as follows.

[0020] [1] Equation (B):

[0021] [Chemical Formula 2]

[0022]

[0023] (during the meal,

[0024] R 1 is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group;

[0025] R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group; and

[0026] As a method for preparing a compound of n (where n is 5 or 6),

[0027] Equation (A):

[0028] [Chemical Formula 3]

[0029]

[0030] (during food, R 1 , R 2 , R 3 A method comprising an oxidation process of reacting a sulfide derivative of (and n as defined above) with hydrogen peroxide in the presence of a metal catalyst.

[0031] [2] R 1 This is a C1-C4 haloalkyl group, and

[0032] R 2 and R 3 Each is independently a halogen atom or a C1-C4 alkyl group; and

[0033] The method described in [1] where n is 5 or 6.

[0034] [3] R 1 This is a trifluoromethyl group, and

[0035] R 2 is a fluorine atom, and R 3 If it is a chlorine atom,

[0036] or R 2 and R 3 ga is a methyl group; also

[0037] The method described in [1] where n is 5 or 6.

[0038] [4] R 1 This is a trifluoromethyl group, and

[0039] R 2 is a fluorine atom, and

[0040] R 3 is a chlorine atom; also

[0041] The method described in [1] where n is 5.

[0042] [5] R 1 This is a trifluoromethyl group, and

[0043] R 2 and R 3 ga is a methyl group; also

[0044] The method described in [1] where n is 6.

[0045] [6] The metal catalyst is one or more catalysts selected from the group consisting of vanadium catalyst, molybdenum catalyst and titanium catalyst (preferably one or two, more preferably one),

[0046] A method described in any one of [1] to [5].

[0047] [7] The metal catalyst is a vanadium catalyst or a molybdenum catalyst,

[0048] A method described in any one of [1] to [5].

[0049] [8] The metal catalyst is a vanadium catalyst,

[0050] A method described in any one of [1] to [5].

[0051] [9] The metal catalyst is a molybdenum catalyst,

[0052] A method described in any one of [1] to [5].

[0053]

[10] Metal catalyst

[0054] vanadyl acetylacetonate, vanadium(III) acetylacetonate, vanadium(V) oxide, vanadium(V) oxytrichloride,

[0055] Titanyl(IV) acetylacetonate, titanium trichloride, titanium tetrachloride, titanium(IV) tetraisopropoxide,

[0056] Ammonium molybdate, sodium molybdate, potassium molybdate, molybdenum oxide, molybdenum chloride, molybdic acid sulfide, phosphomolybdic acid, sodium phosphomolybdate, ammonium phosphomolybdate, silicate molybdic acid, and sodium silicate molybdate

[0057] One or more catalysts selected from the group consisting of (preferably one or two types, more preferably one type),

[0058] A method described in any one of [1] to [5].

[0059]

[11] Metal catalyst

[0060] Vanadyl acetylacetonate, vanadium(III) acetylacetonate,

[0061] titanyl(IV) acetylacetonate, and

[0062] Ammonium molybdate

[0063] One or more catalysts selected from the group consisting of (preferably one or two types, more preferably one type),

[0064] A method described in any one of [1] to [5].

[0065]

[12] Metal catalyst

[0066] Vanadyl acetylacetonate, vanadium(III) acetylacetonate, vanadium(V) oxide, vanadium(V) oxytrichloride,

[0067] Ammonium molybdate, sodium molybdate, potassium molybdate, molybdenum oxide, molybdenum chloride, molybdic acid sulfide, phosphomolybdic acid, sodium phosphomolybdate, ammonium phosphomolybdate, silicate molybdic acid, and sodium silicate molybdate

[0068] One or more catalysts selected from the group consisting of (preferably one or two types, more preferably one type),

[0069] A method described in any one of [1] to [5].

[0070]

[13] Metal catalyst

[0071] Vanadyl acetylacetonate, vanadium(III) acetylacetonate, and

[0072] Ammonium molybdate

[0073] One or more catalysts selected from the group consisting of (preferably one or two types, more preferably one type),

[0074] A method described in any one of [1] to [5].

[0075]

[14] Metal catalyst

[0076] Vanadyl acetylacetonate, vanadium(III) acetylacetonate, vanadium oxide (V), and vanadium oxytrichloride (V)

[0077] One or more catalysts selected from the group consisting of (preferably one or two types, more preferably one type),

[0078] A method described in any one of [1] to [5].

[0079]

[15] Metal catalyst

[0080] Vanadyl acetylacetonate, and vanadium(III) acetylacetonate

[0081] One or more catalysts selected from the group consisting of (preferably one or two types, more preferably one type),

[0082] A method described in any one of [1] to [5].

[0083]

[16] The metal catalyst is vanadyl acetylacetonate,

[0084] A method described in any one of [1] to [5].

[0085]

[17] Metal catalyst

[0086] Ammonium molybdate, sodium molybdate, potassium molybdate, molybdenum oxide, molybdenum chloride, molybdic acid sulfide, phosphomolybdic acid, sodium phosphomolybdate, ammonium phosphomolybdate, silicate molybdic acid, and sodium silicate molybdate

[0087] One or more catalysts selected from the group consisting of (preferably one or two types, more preferably one type),

[0088] A method described in any one of [1] to [5].

[0089]

[18] The metal catalyst is ammonium molybdate,

[0090] A method described in any one of [1] to [5].

[0091]

[19] The above oxidation process is carried out in a solvent,

[0092] [1] to

[18] Method described in [1] to

[18] .

[0093]

[20] In the above oxidation process, the concentration of the compound of formula (A) at the start of the reaction is 5 to 75 weight%,

[0094] The method described in

[19] .

[0095]

[21] In the above oxidation process, the concentration of the compound of formula (A) at the start of the reaction is 20 to 60 weight%,

[0096] The method described in

[19] .

[0097]

[22] In the above oxidation process, the concentration of the compound of formula (A) at the start of the reaction is 35 to 50 weight%,

[0098] The method described in

[19] .

[0099]

[23] A solvent that has high solubility of the compound of formula (A) and low solubility of the compound of formula (B),

[0100]

[19] to

[22] A method described in any one of these.

[0101]

[24] A solvent in which the solubility of the compound of formula (B) is 55% by weight or less in the range of 15 to 20°C,

[0102]

[19] to

[23] A method described in any one of these.

[0103]

[25] A solvent in which the solubility of the compound of formula (B) is 40% by weight or less in the range of 15 to 20°C,

[0104]

[19] to

[23] A method described in any one of these.

[0105]

[26] The solvent is a solvent in which the solubility of the compound of formula (B) is 5 to 75 weight percent in the range of 15 to 20°C,

[0106]

[19] to

[23] A method described in any one of these.

[0107]

[27] The solvent is a solvent in which the solubility of the compound of formula (B) is 20 to 55% by weight in the range of 15 to 20°C,

[0108]

[19] to

[23] A method described in any one of these.

[0109]

[28] The solvent is a solvent in which the solubility of the compound of formula (B) is 30 to 40 weight percent in the range of 15 to 20°C,

[0110]

[19] to

[23] A method described in any one of these.

[0111]

[29] A solvent in which the solubility of the compound of formula (A) is 10% by weight or more in the range of 15 to 20°C,

[0112]

[19] to

[28] Method described in any one of these.

[0113]

[30] A solvent in which the solubility of the compound of formula (A) is 30% by weight or more in the range of 15 to 20°C,

[0114]

[19] to

[28] Method described in any one of these.

[0115]

[31] A solvent in which the solubility of the compound of formula (A) is 40% by weight or more in the range of 15 to 20°C,

[0116]

[19] to

[28] Method described in any one of these.

[0117]

[32] A solvent that contains alcohol,

[0118]

[19] to

[31] The method described in any one of paragraphs 1.

[0119]

[33] The solvent is an alcohol or a mixture of alcohol and water (preferably a mixture of alcohol and water),

[0120]

[19] to

[31] A method described in any one of these.

[0121]

[34] The alcohol is a C1-C6 aliphatic alcohol (preferably a C1-C5 aliphatic alcohol),

[0122]

[32] or

[33] the method described in either one.

[0123]

[35] Alcohols are C1-C4 aliphatic alcohols,

[0124]

[32] or

[33] the method described in either one.

[0125]

[36] The alcohol is methanol, ethanol, 2-propanol, t-butanol, or t-amyl alcohol (preferably methanol, ethanol, 2-propanol, or t-butanol),

[0126]

[32] or

[33] the method described in either one.

[0127]

[37] The alcohol is methanol, 2-propanol, t-butanol, or t-amyl alcohol,

[0128]

[32] or

[33] the method described in either one.

[0129]

[38] The alcohol is 2-propanol, t-butanol, or t-amyl alcohol (preferably 2-propanol or t-butanol),

[0130]

[32] or

[33] the method described in either one.

[0131]

[39] The alcohol is t-butanol or t-amyl alcohol,

[0132]

[32] or

[33] the method described in either one.

[0133]

[40] The alcohol is t-butanol,

[0134]

[32] or

[33] the method described in either one.

[0135]

[41] The solvent is a nitrile solvent or an alcohol solvent, or a mixture of a nitrile solvent or an alcohol solvent and water,

[0136]

[19] to

[31] The method described in any one of paragraphs 1.

[0137]

[42] The solvent is a mixture of acetonitrile, methanol, 2-propanol, t-butanol or t-amyl alcohol, or its water (preferably a mixture of acetonitrile, 2-propanol, t-butanol or t-amyl alcohol, or its water) (more preferably a mixture of acetonitrile, 2-propanol or t-butanol, or its water) (more preferably a mixture of t-butanol and water, or a mixture of t-amyl alcohol and water) (particularly preferably a mixture of t-butanol and water)

[0138]

[19] to

[31] A method described in any one of these.

[0139]

[43] The solvent is acetonitrile, or a mixture of acetonitrile and water (preferably a mixture of acetonitrile and water),

[0140]

[19] to

[31] A method described in any one of these.

[0141]

[44] The solvent is a halogenated solvent, or a mixture of a halogenated solvent and water,

[0142]

[19] to

[31] A method described in any one of these.

[0143]

[45] The solvent is dichloromethane, or a mixture of dichloromethane and water (preferably a mixture of dichloromethane and water),

[0144]

[19] to

[31] A method described in any one of these.

[0145]

[46] Adding an aqueous hydrogen peroxide solution to a solution containing the compound of formula (A) and a metal compound,

[0146] A method described in any one of [1] to

[45] .

[0147]

[47] The oxidation process is carried out at -10°C to 60°C,

[0148] A method described in any one of [1] to

[46] .

[0149]

[48] ​​The oxidation process is carried out at 10°C to 35°C,

[0150] A method described in any one of [1] to

[46] .

[0151]

[49] The oxidation process is carried out at 25°C to 35°C,

[0152] A method described in any one of [1] to

[46] .

[0153]

[50] The oxidation process is carried out at 15°C to 20°C,

[0154] A method described in any one of [1] to

[46] .

[0155]

[51] The rate of adding hydrogen peroxide is 0.5 mol / hour or less (preferably 0.1 mol / hour to 0.5 mol / hour) per mole of the sulfide derivative of formula (A),

[0156] A method described in any one of [1] to

[50] .

[0157]

[52] The rate of adding hydrogen peroxide is 0.05 mol / hour to 0.5 mol / hour per mole of the sulfide derivative of formula (A),

[0158] A method described in any one of [1] to

[50] .

[0159]

[53] The above oxidation process is carried out for 3 hours or more (or 6 hours or more),

[0160] A method described in any one of [1] to

[52] .

[0161]

[54] The oxidation process above is carried out for 48 hours or less (or 24 hours or less),

[0162] A method described in any one of [1] to

[53] .

[0163]

[55] In the above oxidation process, crystals of the compound of formula (B) are precipitated,

[0164] A method described in any one of [1] to

[54] .

[0165]

[56] In the above oxidation process or after the above oxidation process, crystals of the compound of formula (B) are precipitated,

[0166] A method described in any one of [1] to

[54] .

[0167]

[57] A process comprising, after the above oxidation process, precipitating crystals of the compound of formula (B),

[0168] A method described in any one of [1] to

[54] .

[0169]

[58] A process comprising precipitating crystals of the compound of formula (B) in the oxidation process above, or precipitating crystals of the compound of formula (B) after the process above,

[0170] A method described in any one of [1] to

[54] .

[0171]

[59] After the oxidation process above, a process for recovering crystals of the compound of formula (B),

[0172] [1] to

[58] A method described in any one of these.

[0173]

[60] The yield of the compound of formula (B) in the oxidation process is 85 to 100%,

[0174] [1] to

[59] A method described in any one of these.

[0175]

[61] In the oxidation process, the yield of the compound of formula (B) is 90 to 100%,

[0176] [1] to

[59] A method described in any one of these.

[0177]

[62] In the above oxidation process, ligands are not used,

[0178] A method described in any one of [1] to

[61] .

[0179]

[63] The method described in

[62] , in which the ligands are (E)-2-{{(1-hydroxy-2-methylpropane-2-yl)imino}methyl}phenol and (S)-(2,4-di-tert-butyl-6-{(E)-[(1-hydroxy-3,3-dimethylbutane-2-yl)imino]methyl}phenol.

[0180]

[64] The above ligand is, formula (D):

[0181] [Chemical Formula 4]

[0182]

[0183] (during food, R 4 and R 5Each is independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a phenyl C1-C6 alkyl group, a C6-C10 aryl group, a cyano group, a nitro group, or a C1-C6 alkoxy group, and

[0184] R 6 is a C1-C4 alkyl group, cyano group, nitro group, carboxyl group, C1-C4 alkoxycarbonyl group, C1-C4 alkylcarbonyl group, hydroxyC1-C4 alkyl group, C1-C4 alkoxyC1-C4 alkyl group, aminoC1-C4 alkyl group, cyanoC1-C4 alkyl group, nitroC1-C4 alkyl group, carboxyC1-C4 alkyl group, or C1-C4 alkoxycarbonylC1-C4 alkyl group, and

[0185] R 71 and R 72 Each is independently a hydrogen atom, a C1-C6 alkyl group, a phenyl C1-C6 alkyl group, or a C6-C10 aryl group)

[0186] The method described in

[62] , which is a compound of

[0187]

[65] In the above process, carboxylic acid derivatives are not used,

[0188] A method described in any one of [1] to

[64] .

[0189]

[66] In the above process, benzoic acid derivatives are not used,

[0190] A method described in any one of [1] to

[65] .

[0191]

[67] The above benzoic acid derivative,

[0192] Equation (E):

[0193] [Chemical Formula 5]

[0194]

[0195] (during food, A 1 , A 2 , A 3 , A 4 and A 5Each is independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxyl group, or a nitro group;

[0196] M is a hydrogen atom, an alkali metal atom, or an alkaline earth metal atom;

[0197] n is 1 or 2) is a compound,

[0198] The method described in

[66] .

[0199]

[68] The above benzoic acid derivative is sodium 2,6-dimethoxybenzoate,

[0200] The method described in

[66] .

[0201]

[69] In the above oxidation process, the amount of hydrogen peroxide used is 1.0 to 1.5 moles per mole of the sulfide derivative of formula (A),

[0202] [1] to

[68] A method described in any one of these.

[0203]

[70] A method described in any one of [1] to

[69] in which the amount of metal catalyst used in the oxidation process is 0.4 to 3.0 mol% as a metal atom per 1 mole of the sulfide derivative of formula (A).

[0204]

[71] Formula (C):

[0205]

[0206] (during the meal,

[0207] R 1 is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group;

[0208] R 2 and R 3Each is independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

[0209] n is 5 or 6)

[0210] A method described in any one of [1] to

[70] in which the content of the disulfoxide compound is 10% or less of the weight of the compound of formula (B).

[0211]

[72] As described in

[71] ,

[0212] A method in which the content of the disulfoxide derivative of formula (C) is 0% to 10%.

[0213]

[73] As described in

[71] ,

[0214] A method in which the content of the disulfoxide derivative of formula (C) is 0% to 5%.

[0215]

[74] As described in

[71] ,

[0216] A method in which the content of the disulfoxide derivative of formula (C) is 0% to 2%.

[0217]

[75] As a method described in

[71] ,

[0218] A method in which the content of the disulfoxide derivative of formula (C) is 0% to 1%.

[0219]

[76] Formula (B):

[0220]

[0221] (during the meal,

[0222] R 1 is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group;

[0223] R 2 and R 3Each is independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

[0224] n is 5 or 6)

[0225] As a monosulfoxide derivative of,

[0226] Formula (C):

[0227]

[0228] (during the meal,

[0229] R 1 is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group;

[0230] R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

[0231] n is 5 or 6)

[0232] A monosulfoxide derivative in which the content of the disulfoxide compound is 10% or less relative to the weight of the compound of formula (B).

[0233]

[77] As a monosulfoxide derivative described in

[76] ,

[0234] A monosulfoxide derivative having a content of 0% to 10% of the disulfoxide derivative of formula (C).

[0235]

[78] As a monosulfoxide derivative described in

[76] ,

[0236] A monosulfoxide derivative having a content of 0% to 5% of the disulfoxide derivative of formula (C).

[0237]

[79] As a monosulfoxide derivative described in

[76] ,

[0238] A monosulfoxide derivative having a content of 0% to 2% of the disulfoxide derivative of formula (C).

[0239]

[80] As a monosulfoxide derivative described in

[76] ,

[0240] A monosulfoxide derivative having a content of 0% to 1% of the disulfoxide derivative of formula (C).

[0241]

[81] Solid, formula (B):

[0242]

[0243] (Here, R 1 , R 2 , R 3 and n is as defined in [1])

[0244] Monosulfoxide derivative of

[0245]

[82] Crystalline solid, formula (B):

[0246]

[0247] (Here, R 1 , R 2 , R 3 and n is as defined in [1])

[0248] Monosulfoxide derivative of

[0249]

[83] Solid at 25℃, Formula (B):

[0250]

[0251] (Here, R 1 , R 2 , R 3 and n is as defined in [1])

[0252] Monosulfoxide derivative of

[0253]

[84] Formula (B), having a melting point of 40°C to 50°C:

[0254]

[0255] (Here, R 1 , R 2 , R 3 and n is as defined in [1])

[0256] Monosulfoxide derivative of

[0257]

[85] Formula (B), having a melting point of 46°C to 50°C:

[0258]

[0259] (Here, R 1 , R 2 , R 3 and n is as defined in [1])

[0260] Monosulfoxide derivative of

[0261]

[86] Formula (B), having a melting point of 41°C to 45°C:

[0262]

[0263] (Here, R 1 , R 2 , R 3 and n is as defined in [1])

[0264] Monosulfoxide derivative of

[0265]

[87] As a monosulfoxide derivative described in any one of

[76] to

[86] ,

[0266] R 1 This is a C1-C4 haloalkyl group, and

[0267] R 2 and R 3 Each is independently a halogen atom or a C1-C4 alkyl group; also

[0268] Monosulfoxide derivatives in which n is 5 or 6.

[0269]

[88] As a monosulfoxide derivative described in any one of

[76] to

[86] ,

[0270] R 1This is a trifluoromethyl group, and

[0271] R 2 is a fluorine atom and also R 3 is a chlorine atom, or R 2 and R 3 ga is a methyl group; also

[0272] Monosulfoxide derivatives in which n is 5 or 6.

[0273]

[89] As a monosulfoxide derivative described in any one of

[76] to

[86] ,

[0274] R 1 This is a trifluoromethyl group, and

[0275] R 2 is a fluorine atom, and

[0276] R 3 is a chlorine atom; also

[0277] A monosulfoxide derivative in which n is 5.

[0278]

[90]

[76] to

[86] As a monosulfoxide derivative described in any one of

[90]

[76] to

[86] ,

[0279] R 1 This is a trifluoromethyl group, and

[0280] R 2 and R 3 ga is a methyl group; also

[0281] A monosulfoxide derivative in which n is 6.

[0282]

[91]

[0283] A method described in any one of [1] to

[90] in which the compound of formula (B) is a crystal.

[0284]

[92]

[0285] Formula (B):

[0286]

[0287] (during the meal,

[0288] R 1is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group;

[0289] R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, a C2-C4 haloalkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

[0290] n is 5 or 6)

[0291] As a compound of,

[0292] Formula (C):

[0293]

[0294] (during the meal,

[0295] R 1 is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group;

[0296] R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, a C2-C4 haloalkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also

[0297] n is 5 or 6)

[0298] A compound of formula (B) in which the content of the compound is 10% or less relative to the weight of the compound of formula (B).

[0299]

[93]

[0300] Determination of the compound of formula (Ba), characterized in that the powder X-ray diffraction spectrum has characteristic peaks at diffraction angles 2θ = 8.9°±0.2°, 10.3°±0.2°, 13.6°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 20.5°±0.2°, 21.8°±0.2°, 22.3°±0.2°, 23.5°±0.2°, 27.2°±0.2°, 30.9°±0.2°, 33.8°±0.2°, and 37.3°±0.2°.

[0301] Effects of the invention

[0302] According to the present invention, a novel method for manufacturing a monosulfoxide derivative of formula (B) that is useful as a mite killer, etc., which can be industrially applied is provided. According to the present invention, a method for manufacturing a sulfoxide derivative is provided that can solve one or more of the aforementioned defects or problems in the prior art. Accordingly, a method that is inexpensive and can reduce environmental burden can be provided.

[0303] For example, sulfoxide derivatives can be prepared using hydrogen peroxide, which is attracting attention as a clean and excellent oxidizing agent, instead of using metachloroperbenzoic acid as an oxidizing agent.

[0304] In addition, a simple and inexpensive manufacturing method that does not use ligands and benzoic acid derivatives can be provided. Therefore, the cumbersome task of removing ligands and benzoic acid derivatives can also be avoided.

[0305] Furthermore, the cumbersome operation of removing the metal used as a catalyst can be avoided.

[0306] In addition, a method can be provided to selectively and with high yield produce only the desired monosulfoxide derivative from a sulfide derivative having a structural feature of having two oxidized sulfide sites. That is, a selective oxidation reaction can be provided that avoids excessive oxidation.

[0307] Therefore, the method of the present invention is industrially desirable, economical, and environmentally friendly. Brief explanation of the drawing

[0308] [Fig. 1] This is the powder X-ray diffraction spectrum of the crystal of the compound of formula (Ba) obtained in Example 20. White crystals of the compound of formula (Ba) were obtained by the same preparation method as in Example 16. Here, the crystals obtained in the same manner as in Example 16 were used as seed crystals. The obtained crystals were vacuum dried. The melting point was 46°C to 50°C. The obtained crystals were subjected to powder X-ray diffraction. The results of the powder X-ray diffraction measurement are shown in Figure 1. [Fig. 2] This is the powder X-ray diffraction spectrum of the crystal of the compound of formula (Ba) obtained in Example 21. White crystals of the compound of formula (Ba) were obtained by the same preparation method as in Example 16. Here, the crystals obtained in the same manner as in Example 16 were used as seed crystals. The obtained crystals were melted, moisture was removed by vacuum drying, and then cooled. The obtained crystals were milled. The melting point was 47°C to 48°C. The obtained crystals were subjected to powder X-ray diffraction. The results of the powder X-ray diffraction measurement are shown in Figure 2. [Fig. 3] This is the powder X-ray diffraction spectrum of the crystal of the compound of formula (Ba) obtained in Example 22. White crystals of the compound of formula (Ba) were obtained using the same preparation method as in Example 1. Recrystallization was performed on the obtained crystals. Here, the conditions for recrystallization were the same as those for crystallization in Example 1 (recrystallization from 2-propanol and water). The obtained crystals were filtered and dried. The melting point was 46°C to 50°C. The obtained crystals were subjected to powder X-ray diffraction. The results of the powder X-ray diffraction measurement are shown in Figure 3. Specific details for implementing the invention

[0309] The present invention will be described in detail below.

[0310] The method according to the present invention is the following oxidation process:

[0311] [Chemical Formula 6]

[0312]

[0313] (during food, R 1 , R 2 , R 3 and n is as described in [1] above)

[0314] It is represented as.

[0315] Terms and symbols used in this specification are described below.

[0316] Halogen atoms are fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms. From the perspective of the utility and economic feasibility of the product, desirable examples of halogen atoms are fluorine atoms and chlorine atoms.

[0317] Examples of alkali metal atoms include lithium atoms, sodium atoms, potassium atoms, rubidium atoms and cesium atoms, preferably lithium atoms, sodium atoms, potassium atoms and cesium atoms, more preferably lithium atoms, sodium atoms and potassium atoms.

[0318] Examples of alkaline earth metal atoms include magnesium atoms, calcium atoms, strontium atoms, and barium atoms, preferably magnesium atoms, calcium atoms, and barium atoms.

[0319] "Ca-Cb" means that the number of carbon atoms is a to b. For example, "C1-C4" in "C1-C4 alkyl group" means that the number of carbon atoms in the alkyl group is 1 to 4.

[0320] In this specification, general terms such as “alkyl” are interpreted to include both straight-chain and branched-chains, such as butyl and tert-butyl. Meanwhile, for example, the specific term “butyl” means straight-chain “normal butyl” and does not mean branched-chain “tert-butyl”. Branched-chain isomers such as “tert-butyl” are specifically mentioned where intended. As another example, the specific term “propyl” means straight-chain “normal propyl” and does not mean branched-chain “isopropyl”. Branched-chain isomers such as “isopropyl” are specifically mentioned where intended.

[0321] In this specification, the following abbreviations and prefixes may be used, and their meanings are as follows.

[0322] Me: Methyl

[0323] Et: Ethyl

[0324] Pr, n-Pr, and Pr-n: Profiles (i.e., normal profiles)

[0325] i-Pr and Pr-i: isopropyl

[0326] Bu, n-Bu and Bu-n: Butyl (i.e., normal butyl)

[0327] s-Bu and Bu-s: sec-butyl (i.e., secondary butyl)

[0328] i-Bu and Bu-i: Isobutyl

[0329] t-Bu and But-t: tert-butyl (i.e., tertiary butyl)

[0330] pH: Phenyl

[0331] n-: normal

[0332] s- and sec-: secondary

[0333] i- and iso-: iso

[0334] t- and tert-: tershuri

[0335] c- and cyc-: cyclo

[0336] o-: Orso

[0337] m-: meta

[0338] p-: Para

[0339] A C1-C6 alkyl group refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms.

[0340] Examples of C1-C6 alkyl groups are methyl, ethyl, propyl, and isopropyl groups.

[0341] Butyl group, sec-butyl group, isobutyl group, tert-butyl group,

[0342] It includes pentyl groups, hexyl groups, etc., but is not limited to these.

[0343] A C1-C4 alkyl group refers to a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms.

[0344] An example of a C1-C4 alkyl group is a suitable example among the examples of the above C1-C4 alkyl groups.

[0345] A C2-C4 alkenyl group means a straight or branched alkenyl group having 2 to 6 carbon atoms. Examples of C2-C4 alkenyl groups include, but are not limited to, vinyl groups (i.e., ethenyl groups), 1-propenyl groups, 2-propenyl groups, isopropenyl groups (i.e., 1-methylvinyl groups), 1-butenyl groups, 2-butenyl groups, 3-butenyl groups, 1-methyl-1-propenyl groups, 2-methyl-1-propenyl groups, 1,3-butadienyl groups, etc.

[0346] A C2-C4 alkynyl group means a straight or branched alkynyl group having 2 to 4 carbon atoms. Examples of C2-C4 alkynyl groups include, but are not limited to, ethynyl groups, 1-propynyl groups, 2-propynyl groups, 1-butynyl groups, 2-butynyl groups, 3-butynyl groups, 1-methyl-2-propynyl groups, etc.

[0347] A haloalkyl group means a straight-chain or branched-chain alkyl group substituted by one or more identical or different halogen atoms.

[0348] A C1-C4 haloalkyl group means a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms substituted by 1 to 9 identical or different halogen atoms (wherein, halogen atoms have the same meaning as in the above definition).

[0349] Examples of C1-C4 haloalkyl groups are,

[0350] Fluoromethyl group, difluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group,

[0351] 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group,

[0352] 3-fluoropropyl group, 3-chloropropyl group, 3-bromopropyl group, 2,2,3,3,3-pentafluoropropyl group, 2,2,2-trifluoro-1-trifluoromethylethyl group, heptafluoropropyl group, 1,2,2,2-tetrafluoro-1-trifluoromethylethyl group,

[0353] It includes, but is not limited to, 4-fluorobutyl groups, 4-chlorobutyl groups, 4-bromobutyl groups, 2,2,3,3,4,4,4-heptafluorobutyl groups.

[0354] A C2-C4 haloalkenyl group means a straight or branched alkenyl group having 2 to 4 carbon atoms substituted by 1 to 7 identical or different halogen atoms (wherein, halogen atoms have the same meaning as in the above definition). Examples of C2-C4 haloalkenyl groups include 1-fluorovinyl group, 1-chlorovinyl group, 2-fluorovinyl group, 2-chlorovinyl group, 2,2-difluorovinyl group, trifluorovinyl group, 2-fluoro-2-propenyl group, 2-chloro-2-propenyl group, 3-fluoro-2-propenyl group, 3-chloro-2-propenyl group, 3,3-difluoro-2-propenyl group, 3,3-dichloro-2-propenyl group, 2,3-difluoro-2-propenyl group, 2,3-trifluoro-2-propenyl group, 1-(chloromethyl)vinyl group, 1-(trifluoromethyl)vinyl group, 1-trifluoromethyl-2,2-difluorovinyl group, 4,4-difluoro-3-butenyl group, It includes, but is not limited to, 3,4,4-trifluoro-3-butenyl groups.

[0355] A C2-C4 haloalkynyl group means a straight-chain or branched-chain alkynyl group having 2 to 4 carbon atoms substituted by 1 to 5 identical or different halogen atoms (wherein, halogen atoms have the same meaning as in the above definition). Examples of C2-C4 haloalkynyl groups are 2-fluoroethynyl group, 2-chloroethynyl group, 3-fluoro-1-propynyl group, 3-chloro-1-propynyl group, 1-fluoro-2-propynyl group, 1-chloro-2-propynyl group, 3-fluoro-2-propynyl group, 3-chloro-2-propynyl group, 1,1-difluoro-2-propynyl group, 4-fluoro-3-butynyl group, 4-chloro-3-butynyl group, 4,4-difluoro-2-butynyl group, and 4,4,4-trifluoro-2-butynyl group. It includes, but is not limited to, the following.

[0356] A C1-C4 alkoxy group refers to a (C1-C4 alkyl)-O group (wherein the C1-C4 alkyl portion has the same meaning as the definition above).

[0357] Examples of C1-C4 alkoxy groups include, but are not limited to, methoxy groups, ethoxy groups, propoxy groups, isopropoxy groups, butoxy groups, sec-butoxy groups, isobutoxy groups, tert-butoxy groups, etc.

[0358] A C1-C4 haloalkoxy group refers to a (C1-C4 haloalkyl)-O- group (wherein the C1-C4 haloalkyl group portion has the same meaning as above).

[0359] Examples of C1-C4 haloalkoxy groups are,

[0360] Fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, chlorodifluoromethoxy group,

[0361] 2-fluoroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, pentafluoroethoxy group,

[0362] 3-fluoropropoxy group, 3-chloropropoxy group, 3-bromopropoxy group, 2,2,3,3,3-pentafluoropropoxy group, 2,2,2-trifluoro-1-trifluoromethylethoxy group, heptafluoropropoxy group, 1,2,2,2-tetrafluoro-1-trifluoromethylethoxy group,

[0363] It includes, but is not limited to, 4-fluorobutoxy groups, 4-chlorobutoxy groups, 4-bromobutoxy groups, 2,2,3,3,4,4,4-heptafluorobutoxy groups.

[0364] A phenyl C1-C6 alkyl group refers to a C1-C6 alkyl group substituted by a phenyl group (wherein the C1-C6 alkyl group portion has the same meaning as the definition above).

[0365] Examples of phenyl C1-C6 alkyl groups include, but are not limited to, benzyl groups, 1-phenylethyl groups, 2-phenylethyl groups, 3-phenylpropyl groups, 4-phenylbutyl groups, 5-phenylpentyl groups, 6-phenylhexyl groups, etc.

[0366] A C6-C10 aryl group refers to an aromatic cyclic group in which all atoms constituting the ring are 6 to 10 carbon atoms.

[0367] Examples of C6-C10 aryl groups are the phenyl group, 1-naphthyl group, and 2-naphthyl group. The 1-naphthyl group is also called the naphthalene-1-yl group. The 2-naphthyl group is also called the naphthalene-2-yl group.

[0368] A C1-C4 alkoxycarbonyl group refers to a (C1-C4 alkyl)-OC(=O)- group (where the C1-C4 alkyl portion has the same meaning as the definition above).

[0369] Examples of C1-C4 alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl groups, ethoxycarbonyl groups, propoxycarbonyl groups, isopropoxycarbonyl groups, butoxycarbonyl groups.

[0370] A C1-C4 alkyl carbonyl group refers to a (C1-C4 alkyl)-C(=O)- group (where the C1-C4 alkyl group portion has the same meaning as the definition above).

[0371] Examples of C1-C4 alkyl carbonyl groups include, but are not limited to, acetyl groups, propionyl groups, butyryl groups, isobutyryl groups, valeryl groups, etc.

[0372] A hydroxy C1-C4 alkyl group refers to a C1-C4 alkyl group substituted by a hydroxyl group (wherein, the C1-C4 alkyl group has the same meaning as above).

[0373] Examples of hydroxy C1-C4 alkyl groups include, but are not limited to, hydroxymethyl groups, 1-hydroxyethyl groups, 2-hydroxyethyl groups, 1-hydroxypropyl groups, 2-hydroxypropyl groups, 1-hydroxybutyl groups, 2-hydroxybutyl groups, 3-hydroxybutyl groups.

[0374] A C1-C4 alkoxy C1-C4 alkyl group means a C1-C4 alkyl group substituted by a C1-C4 alkoxy group (wherein, the C1-C4 alkoxy group and the C1-C4 alkyl group have the same meaning as above).

[0375] Examples of C1-C4 alkoxy C1-C4 alkyl groups are,

[0376] Methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxymethyl group,

[0377] 1-methoxyethyl group, 2-methoxyethyl group, 1-ethoxyethyl group, 2-ethoxyethyl group, 1-propoxyethyl group, 2-propoxyethyl group, 1-isopropoxyethyl group, 2-isopropoxyethyl group,

[0378] 1-methoxypropyl group, 2-methoxypropyl group, 3-methoxypropyl group,

[0379] It includes, but is not limited to, 1-methoxybutyl groups, 2-methoxybutyl groups, 3-methoxybutyl groups, 4-methoxybutyl groups, etc.

[0380] An amino C1-C4 alkyl group refers to a C1-C4 alkyl group substituted by an amino group (wherein, the C1-C4 alkyl group has the same meaning as above).

[0381] Examples of amino C1-C4 alkyl groups include, but are not limited to, aminomethyl groups, 1-aminoethyl groups, 2-aminoethyl groups, 1-aminopropyl groups, 2-aminopropyl groups, 1-aminobutyl groups, 2-aminobutyl groups, 3-aminobutyl groups.

[0382] A cyano C1-C4 alkyl group refers to a C1-C4 alkyl group substituted by a cyano group (wherein, the C1-C4 alkyl group has the same meaning as above).

[0383] Examples of cyano-C1-C4 alkyl groups include, but are not limited to, cyanomethyl groups, 1-cyanoethyl groups, 2-cyanoethyl groups, 1-cyanopropyl groups, 2-cyanopropyl groups, 1-cyanobutyl groups, 2-cyanobutyl groups, 3-cyanobutyl groups.

[0384] A nitro C1-C4 alkyl group refers to a C1-C4 alkyl group substituted by a nitro group (wherein, the C1-C4 alkyl group has the same meaning as above).

[0385] Examples of nitro C1-C4 alkyl groups include, but are not limited to, nitromethyl groups, 1-nitroethyl groups, 2-nitroethyl groups, 1-nitropropyl groups, 2-nitropropyl groups, 1-nitrobutyl groups, 2-nitrobutyl groups, 3-nitrobutyl groups.

[0386] A carboxy C1-C4 alkyl group refers to a C1-C4 alkyl group substituted by a carboxyl group (wherein, the C1-C4 alkyl group has the same meaning as above).

[0387] Examples of carboxy C1-C4 alkyl groups include, but are not limited to, carboxymethyl groups, 1-carboxyethyl groups, 2-carboxyethyl groups, 1-carboxypropyl groups, 2-carboxypropyl groups, 1-carboxybutyl groups, 2-carboxybutyl groups, 3-carboxybutyl groups.

[0388] A C1-C4 alkoxycarbonyl C1-C4 alkyl group refers to a C1-C4 alkyl group substituted by a C1-C4 alkoxycarbonyl group (wherein, the C1-C4 alkoxycarbonyl group and the C1-C4 alkyl group have the same meaning as above).

[0389] Examples of C1-C4 alkoxycarbonyl C1-C4 alkyl groups are,

[0390] Methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, isopropoxycarbonylmethyl group,

[0391] 1-methoxycarbonylethyl group, 2-methoxycarbonylethyl group, 1-ethoxycarbonylethyl group, 2-ethoxycarbonylethyl group, 1-propoxycarbonylethyl group, 2-propoxycarbonylethyl group, 1-isopropoxycarbonylethyl group, 2-isopropoxycarbonylethyl group,

[0392] 1-Methoxycarbonylpropyl group, 2-Methoxycarbonylpropyl group, 3-Methoxycarbonylpropyl group,

[0393] It includes, but is not limited to, 1-methoxycarbonylbutyl group, 2-methoxycarbonylbutyl group, 3-methoxycarbonylbutyl group, 4-methoxycarbonylbutyl group, etc.

[0394] The term (C1-C4 alkyl)amino group refers to the (C1-C4 alkyl)-NH group (wherein the C1-C4 alkyl portion has the same meaning as the definition above).

[0395] Examples of (C1-C4 alkyl)amino groups include, but are not limited to, methylamino groups, ethylamino groups, propylamino groups, isopropylamino groups, butylamino groups.

[0396] Definitions and examples of functional groups other than those mentioned above can be understood by those skilled in the art, just like the functional groups mentioned above.

[0397] In this specification, compounds having isomers include all isomers and any mixture of them in any proportion. For example, xylene includes o-xylene, m-xylene, p-xylene, and any mixture of them in any proportion. For example, dichlorobenzene includes o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, and any mixture of them in any proportion.

[0398] In this specification, the non-limiting term “comprise(s) / comprising” may be optionally replaced with the limiting phrase “consist(s) of / consisting of”.

[0399] In this specification, the terms “recover / recover” may be optionally replaced with “separate / separate”. In this specification, the sulfide derivative of formula (A) is synonymous with the compound of formula (A), the monosulfoxide derivative of (B) is synonymous with the compound of (B), and the disulfoxide derivative of formula (C) is synonymous with the compound of formula (C).

[0400] Unless otherwise specified, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains.

[0401] Unless otherwise indicated, numbers representing characteristics such as quantity, size, concentration, reaction conditions used herein are understood to be modified by the term “about.” In some embodiments, the disclosed figures are interpreted by applying the reported number of significant figures and conventional rounding techniques. In some embodiments, the disclosed figures are interpreted to include errors inevitably arising from the standard deviations in each test measurement method.

[0402] (Raw compound: Sulfide derivative of Formula (A))

[0403] The preparation of the sulfide derivative of formula (A) may be carried out, for example, as described in International Publication No. 2013 / 157229 (Patent Document 1) or by a similar method.

[0404] [Chemical Formula 7]

[0405]

[0406] Specific examples of sulfide derivatives of formula (A) and the preparation of compounds of (Aa) are shown in the figure below.

[0407] [Chemical Formula 8]

[0408]

[0409] In terms of the usefulness and economic feasibility of the product, R in Equation (A) 1 , R 2 , R 3 The desirable combination of and n is:

[0410] R 1 This is a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkinyl group;

[0411] R 2 and R 3 Each is independently a halogen atom or a C1-C4 alkyl group; also

[0412] n is 5 or 6.

[0413] In the same regard as above, R in Equation (A) 1 , R 2 , R 3 A more desirable combination of and n is:

[0414] R 1 This is a C1-C4 haloalkyl group;

[0415] R 2 and R 3 Each is independently a halogen atom or a C1-C4 alkyl group; also

[0416] n is 5 or 6.

[0417] In the same regard as above, R in Equation (A) 1 , R 2 , R 3 A more desirable combination of and n is:

[0418] R 1 This is a trifluoromethyl group;

[0419] R 2 is a fluorine atom;

[0420] R 3 is a chlorine atom, or

[0421] R 2 and R 3 ga is a methyl group; also

[0422] n is 5 or 6.

[0423] In one sun, from the above perspective, R in Equation (A) 1 , R 2 , R 3 A more desirable specific combination of and n is:

[0424] R 1 This is a trifluoromethyl group;

[0425] R 2 is a fluorine atom;

[0426] R 3 is a chlorine atom; also

[0427] n is 5.

[0428] In the other sun, from the same perspective as above, R in Equation (A) 1 , R 2 , R 3 A more desirable specific combination of and n is:

[0429] R 1 This is a trifluoromethyl group;

[0430] R 2 and R 3 ga is a methyl group; also

[0431] n is 6.

[0432] In the same regard as above, R in Equation (A) 1 , R 2 , R 3 A particularly desirable specific combination of and n is:

[0433] R 1 This is a trifluoromethyl group;

[0434] R 2 is a fluorine atom;

[0435] R 3 is a chlorine atom; also

[0436] n is 5.

[0437] (Target compound: monosulfoxide derivative of formula (B))

[0438] In the same regard as above, R in Equation (B) 1 , R 2 , R 3 The preferred combinations of and n, more specific combinations, more preferred combinations, and particularly preferred combinations are identical to those in the above-described formula (A).

[0439] A particularly desirable specific example of a compound of formula (B) is a compound of formula (Ba) below.

[0440] [Chemical Formula 9]

[0441]

[0442] As described above, in a method for preparing a monosulfoxide derivative of formula (B) from a compound of formula (A), it is desired that the oxidation reaction proceeds sufficiently and that the proportion of the disulfoxide derivative of formula (C) in the product is sufficiently low. The content of the compound of formula (C) in the reaction mixture after the oxidation reaction may be, for example, 10% or less (0% to 10%), preferably 0% to 7%, more preferably 0% to 5%, even more preferably 0% to 3%, even more preferably 0% to 2%, and particularly preferably 0% to 1% with respect to the weight of the compound of formula (B).

[0443] (Oxidizing agent; hydrogen peroxide)

[0444] Any oxidizing agent used in the present invention may be used as long as the reaction proceeds. An oxidizing agent capable of oxidizing a corresponding raw material compound (sulfide derivative) into a target compound (monosulfoxide derivative) may be used. Examples of oxidizing agents used in the present invention include, but are not limited to, inorganic peroxides (e.g., hydrogen peroxide, urea-hydrogen peroxide adducts, etc.). Hydrogen peroxide is a preferred oxidizing agent in terms of safety, reactivity, selectivity, and economic efficiency. The oxidizing agent may be used alone or in a combination of two or more in any proportion.

[0445] An oxidizing agent is used in the present invention. The form of the oxidizing agent may be any form as long as the reaction proceeds. The form of the oxidizing agent can be appropriately selected by a person skilled in the art. When hydrogen peroxide is used as the oxidizing agent, the form of the hydrogen peroxide may be any form as long as the reaction proceeds. Considering safety, risk, economic efficiency, etc., examples of preferred forms of hydrogen peroxide include a 5 to 60 wt% aqueous hydrogen peroxide solution, preferably a 5 to 40 wt% aqueous hydrogen peroxide solution, more preferably a 10 to 35 wt% aqueous hydrogen peroxide solution, and even more preferably a 25 to 35 wt% aqueous hydrogen peroxide solution. Additionally, in this specification, for example, "30% aqueous hydrogen peroxide solution" is also referred to as "30% hydrogen peroxide."

[0446] (Usage of oxidizing agent)

[0447] In the method of the present invention, the amount of oxidizing agent (preferably hydrogen peroxide) used may be any amount as long as the reaction proceeds.

[0448] In terms of improving yield and economic efficiency, the lower limit of the amount of oxidizing agent (preferably hydrogen peroxide) used in the present invention may be, for example, 0.9 moles or more, preferably 1.0 moles or more, per 1 mole of the sulfide derivative (raw material compound) of formula (A).

[0449] From the perspective of safety, suppression of by-products, and economic efficiency, the upper limit of the amount of oxidizing agent (preferably hydrogen peroxide) used in the present invention may be, for example, 2.0 moles or less, preferably 1.7 moles or less, more preferably 1.5 moles or less per 1 mole of the sulfide derivative (raw material compound) of formula (A).

[0450] In addition, the amount of oxidizing agent (preferably hydrogen peroxide) used in the present invention may be any and appropriate combination of the lower and upper limits mentioned above. Accordingly, from the viewpoint of safety, improvement of yield, suppression of by-products, and economic efficiency, the amount of oxidizing agent (preferably hydrogen peroxide) used in the present invention may be, for example, 0.9 to 2.0 moles, preferably 1.0 to 2.0 moles, more preferably 1.0 to 1.7 moles, even more preferably 1.0 to 1.5 moles, and particularly preferably 1.0 to 1.2 moles per mole of the sulfide derivative (raw material compound) of formula (A). However, the amount of oxidizing agent (preferably hydrogen peroxide) used in the present invention may be appropriately adjusted by a person skilled in the art depending on the purpose and circumstances.

[0451] (Metal catalyst)

[0452] The metal catalyst in the present invention will be described. The metal catalyst used in the present invention may be any metal catalyst as long as the reaction proceeds. The metal catalyst used in the present invention is a known compound or a compound that can be prepared from a known compound according to a known method.

[0453] Metal catalysts include metal acetylacetonates, metal oxyacetylacetonates, metal halides, metal oxyhalides, metal oxides, metal alkoxides, etc., but are not limited to these.

[0454] The metal of the metal catalyst is preferably a transition metal.

[0455] Examples of metal catalysts include, but are not limited to, iron catalysts, vanadium catalysts, titanium catalysts, manganese catalysts, copper catalysts, molybdenum catalysts, zirconium catalysts, tungsten catalysts, niobium catalysts, tantalum catalysts, thallium catalysts, etc.

[0456] In terms of yield, suppression of by-products, and economic efficiency, the metal catalyst is preferably one or more selected from the group consisting of vanadium catalyst, molybdenum catalyst and titanium catalyst (preferably one or two types, more preferably one type), more preferably a vanadium catalyst or a molybdenum catalyst, and more preferably a vanadium catalyst.

[0457] Examples of iron catalysts include, but are not limited to, iron(III) acetylacetonate, iron(III) chloride, iron(III) bromide, iron(III) methoxide, iron(III) ethoxide, iron(III) propoxide, iron(III) isopropoxide, iron(III) nitrate, etc. "Iron(III) acetylacetonate" is also called "Fe(acac)3" or "tris(2,4-pentanedionato)iron(III)".

[0458] In the method described in WO2017 / 150478 (Patent Document 2), the reaction mixture became black due to the iron catalyst used. In addition, washing with dilute sulfuric acid several times was required to remove the iron catalyst.

[0459] Examples of vanadium catalysts include, but are not limited to, vanadyl acetylacetonate, vanadium(III) acetylacetonate, vanadium(V) oxytrichloride, vanadium(V) oxide, vanadium(V) oxytriethoxide, triisopropoxyvanadium(V) oxide, etc. "Vanadyl acetylacetonate" is also referred to as "VO(acac)2", "bis(2,4-pentanedionato)vanadium(IV) oxide", or "vanadium(IV) oxyacetylacetonate". "Triisopropoxyvanadium(V) oxide" is also referred to as "VO(OiPr)3" or "triisopropoxyoxovanadium(V)". In the above context, preferred examples of vanadium catalysts include vanadyl acetylacetonate, vanadium (III) acetylacetonate, vanadium oxytrichloride (V), and vanadium oxide (V). More preferred examples of vanadium catalysts include vanadyl acetylacetonate, vanadium (III) acetylacetonate, and vanadium oxide (V). More preferred examples of vanadium catalysts include vanadyl acetylacetonate and vanadium (III) acetylacetonate. A particularly preferred example of a vanadium catalyst is vanadyl acetylacetonate.

[0460] Examples of titanium catalysts include, but are not limited to, titanium tetrachloride, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, titanium (IV) isopropoxide, titanium (IV) tert-butoxide, titanyl (IV) acetylacetonate, etc. "Titanyl (IV) acetylacetonate" is also referred to as "TiO(acac)2", "bis(2,4-pentanedionato)titanium (IV) oxide", or "titanyl (IV) oxyacetylacetonate". In the above context, preferred examples of titanium catalysts include titanium tetrachloride, titanium trichloride, titanium (IV) tetraisopropoxide, and titanyl (IV) acetylacetonate. More preferred examples of titanium catalysts include titanium tetrachloride, titanium trichloride, and titanyl(IV) acetylacetonate. A particularly preferred example of titatitanium is titanyl(IV) acetylacetonate.

[0461] Examples of manganese catalysts include, but are not limited to, potassium permanganate, manganese(III) acetylacetonate, manganese(II) chloride, manganese(II) oxide, etc. "Manganese(III) acetylacetonate" is also called "Mn(acac)3".

[0462] Examples of copper catalysts include, but are not limited to, copper(II) acetylacetonate, copper(I) chloride, copper(II) chloride, copper(I) acetate, copper(II) acetate, copper(I) bromide, copper(I) iodide, etc. "Copper(II) acetylacetonate" is also called "Cu(acac)2".

[0463] Examples of molybdenum catalysts include, but are not limited to, molybdenyl acetylacetonate, molybdic acid, sodium molybdate (including sodium molybdate dihydrate), potassium molybdate, ammonium molybdate (including ammonium molybdate tetrahydrate), molybdenum oxide (e.g., molybdenum oxide (VI)), molybdenum chloride (e.g., molybdenum chloride (V)), molybdenum sulfide (e.g., molybdenum sulfide (IV)), phosphomolybdic acid, sodium phosphomolybdate, ammonium phosphomolybdate, silomolybdic acid, sodium silomolybdate, etc. "Molybdenyl acetylacetonate" is also referred to as "MoO2(acac)2", "bis(2,4-pentanedionato)molybdenum(VI) dioxide", or "molybdenum(IV) dioxacetylacetonate". In the same light as above, preferred examples of molybdenum catalysts include ammonium molybdate, sodium molybdate, potassium molybdate, molybdenum oxide, molybdenum chloride, molybdenum sulfide, phosphomolybdic acid, sodium phosphomolybdate, ammonium phosphomolybdate, silomolybdic acid, and sodium silomolybdate. More preferred examples of molybdenum catalysts include ammonium molybdate, sodium molybdate, potassium molybdate, and molybdenum oxide. More preferred examples of molybdenum catalysts include ammonium molybdate, sodium molybdate, and potassium molybdate. A particularly preferred example of a molybdenum catalyst is ammonium molybdate (e.g., ammonium molybdate tetrahydrate).

[0464] Among molybdenum compounds, ammonium molybdate is a catalyst used for trost oxidation. Trost oxidation is commonly used in reactions to oxidize sulfide compounds to sulfone compounds, as described in the Journal of the American Chemical Society 2009, 131, 47, 17087-17089. However, unexpectedly, in this reaction, the reaction is completed with monosulfoxide compounds, and excessive oxidation to the compound of formula (C) can also be suppressed.

[0465] Examples of zirconium catalysts include, but are not limited to, zirconium (IV) acetylacetonate, zirconium tetrachloride, zirconium oxychloride (e.g., zirconium (IV) oxychloride octahydrate (ZrCl2O·8H2O)). "Zirconium (IV) acetylacetonate" is also called "Zr(acac)4" or "tetrakis(2,4-pentanedionato) zirconium (IV)".

[0466] Examples of tungsten catalysts include, but are not limited to, tungstic acid, sodium tungstate (including sodium tungstate dihydrate and sodium tungstate decahydrate), potassium tungstate, calcium tungstate, ammonium tungstate (including ammonium paratungstate pentahydrate), tungsten oxide (VI) (also called tungsten trioxide), tungsten chloride (VI) (also called tungsten hexachloride), tungsten bromide (V), tungsten sulfide (IV) (also called tungsten disulfide), phosphotungstic acid, sodium phosphotungstate, ammonium phosphotungstate, silicic tungstic acid, sodium silicic tungstate, etc.

[0467] Examples of niobium catalysts include, but are not limited to, niobium carbide, niobium(V) chloride, niobium(V) pentaethoxide, etc.

[0468] Examples of tantalum catalysts include, but are not limited to, tantalum carbide (TaC), tantalum chloride (V) (TaCl5), tantalum (V) pentaethoxide (Ta(OEt)5), etc.

[0469] Examples of thallium catalysts include, but are not limited to, thallium nitrate (III), thallium acetate (III), thallium trifluoroacetate (III), etc. and mixtures thereof.

[0470] The metal compound in the present invention may be used alone or in a combination of two or more in any proportion. The form of the metal catalyst in the present invention may be any form as long as the reaction proceeds. The form of the metal catalyst in the present invention may be appropriately selected by those skilled in the art.

[0471] (Usage of metal catalyst)

[0472] The amount of metal catalyst used in the method of the present invention may be any amount as long as the reaction proceeds. In one embodiment, with respect to the improvement of yield, reduction of environmental burden, and economic efficiency, the amount of metal catalyst used in the present invention may be, for example, 0.1 to 20.0 mol%, preferably 0.1 to 10.0 mol%, more preferably 0.1 to 5.0 mol%, even more preferably 0.1 to 3.0 mol%, even more preferably 0.1 to 2.0 mol%, and even more preferably 0.1 to 1.0 mol% per 1 mol of the sulfide derivative (raw material compound) of formula (A). In addition, in another aspect, from the perspective of the above, for example, the amount of metal compound used in the present invention may be, with respect to 1 mole of the sulfide derivative (raw material compound) of formula (A), preferably 0.3 to 6.0 mol%, more preferably 0.3 to 5.0 mol%, even more preferably 0.4 to 5.0 mol%, even more preferably 0.4 to 4.0 mol%, even more preferably 0.4 to 3.0 mol%, and particularly preferably 0.5 to 2.0 mol% as metal atoms. However, the amount of metal catalyst used in the present invention may be appropriately adjusted by a person skilled in the art depending on the purpose and circumstances.

[0473] (ligand)

[0474] Ligands that are not required in the present invention are described. Even without using ligands, the reaction of the present invention proceeds sufficiently. Therefore, from the perspective of economic efficiency and the like, ligands are preferably not used in the present invention.

[0475] Examples of ligands not used in the present invention are formula (D):

[0476] [Chemical Formula 10]

[0477]

[0478] (during food, R 4 , R 5 , R 6 , R 71 and R 72 is as follows)

[0479] It includes, but is not limited to, compounds of

[0480] In equation (D), R 4 and R 5 Each is independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a phenyl C1-C6 alkyl group, a C6-C10 aryl group, a cyano group, a nitro group, or a C1-C6 alkoxy group.

[0481] In equation (D), R 6 is a C1-C4 alkyl group, cyano group, nitro group, carboxyl group, C1-C4 alkoxycarbonyl group, C1-C4 alkylcarbonyl group, hydroxyC1-C4 alkyl group, C1-C4 alkoxyC1-C4 alkyl group, aminoC1-C4 alkyl group, cyanoC1-C4 alkyl group, nitroC1-C4 alkyl group, carboxyC1-C4 alkyl group, or C1-C4 alkoxycarbonylC1-C4 alkyl group.

[0482] In equation (D), R 71 and R 72 Each is independently a hydrogen atom, a C1-C6 alkyl group, a phenyl C1-C6 alkyl group, or a C6-C10 aryl group.

[0483] Specific examples of ligands not used in the present invention are shown below.

[0484] For example, 2,4-di-t-butyl-6-{(E)-[(1-hydroxy-3,3-dimethylbutane-2-yl)imino]methyl}phenol described in WO2011 / 006646 (Patent Document 3), and compounds (3-1) to (3-13) described in WO2017 / 150478 (Patent Document 2), i.e.,

[0485] (E)-2-{[(1-hydroxy-3-methylbutane-2-yl)imino]methyl}phenol, (E)-2-{[(1-hydroxybutane-2-yl)imino]methyl}phenol, (E)-2-{[(1-hydroxypropane-2-yl)imino]methyl}phenol, (E)-2-{[(1-hydroxy-2-methylpropane-2-yl)imino]methyl}phenol, (E)-2-{[(2-hydroxyethyl)imino]methyl}phenol, (E)-2-{[(1-hydroxy-2-methylpropane-2-yl)imino]methyl}-4-methylphenol, (E)-2-{[(1-hydroxy-2-methylpropane-2-yl)imino]methyl}-4-methoxyphenol, (E)-4-fluoro-2-{[(1-hydroxy-2-methylpropane-2-yl)imino]methyl}phenol, (E)-4-chloro-2-{[(1-hydroxy-2-methylpropane-2-yl)imino]methyl}phenol, (E)-4-bromo-2-{[(1-hydroxy-2-methylpropane-2-yl)imino]methyl}phenol, (E)-2-{[(1-hydroxy-2-methylpropane)-2-yl)imino]methyl}-4-iodophenol, (E)-2-{[(2-hydroxy-1-phenylethyl)imino]methyl}phenol, (E)-4-chloro-2-{[(1-hydroxy-3-methylbutane-2-yl)imino]methyl}phenol, (E)-4-chloro-2-{[(2-hydroxyethyl)imino]methyl}phenol,

[0486] Compounds 1a to 1d described in Chemical European Journal, 2005, 11, 1086-1092, J. Legros et al, i.e.,

[0487] (E)-2-{[(1-hydroxy-3,3-dimethylbutanone-2-yl)imino]methyl}-4,6-diiodophenol, (E)-2-{[(1-hydroxy-3,3-dimethylbutanone-2-yl)imino]methyl}-4,6-dibromophenol, (E)-2-{[(1-hydroxy-3,3-dimethylbutanone-2-yl)imino]methyl}phenol, (E)-2-{[(1-hydroxy-3-methylbutanone-2-yl)imino]methyl}-4,6-diiodophenol, etc., but are not limited to these.

[0488] (Benzoic acid derivative)

[0489] Benzoic acid derivatives that do not need to be used in the present invention are described. The reaction of the present invention proceeds sufficiently even without using carboxylic acid derivatives such as benzoic acid derivatives. Therefore, from the perspective of economic efficiency, carboxylic acid derivatives such as benzoic acid derivatives are preferably not used in the present invention.

[0490] Examples of benzoic acid derivatives not used in the present invention are formula (E):

[0491] [Chemical Formula 11]

[0492]

[0493] (during food, A 1 , A 2 , A 3 , A 4 , A 5 , M and n are as follows)

[0494] It includes, but is not limited to, compounds of

[0495] Among Equation (E),

[0496] A 1 This is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxyl group, or a nitro group;

[0497] A 2 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxyl group, or a nitro group;

[0498] A 3 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxyl group, or a nitro group;

[0499] A 4 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxyl group, or a nitro group;

[0500] A5 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a (C1-C4 alkyl)amino group, a hydroxyl group, or a nitro group.

[0501] In formula (E), M is a hydrogen atom, an alkali metal atom, or an alkaline earth metal atom.

[0502] Specific examples of M include, but are not limited to, hydrogen atoms, lithium atoms, sodium atoms, potassium atoms, cesium atoms, magnesium atoms, calcium atoms, and barium atoms.

[0503] In Equation (E), n is 1 or 2. More specifically, as long as it is chemically permissible, n can be 1 or 2. For example, when M is a hydrogen atom or an alkali metal atom, n is 1. As another example, when M is an alkaline earth metal atom, n is 2.

[0504] Specific examples of carboxylic acid derivatives, such as benzoic acid derivatives not used in the present invention, are shown below.

[0505] For example, the benzoic acid derivatives of (4-1) to (4-19) described in WO2017 / 150478 (Patent Document 2), namely, sodium 2,6-dimethoxybenzoate, sodium 2,4,6-trimethoxybenzoate, sodium 2,4-dimethoxybenzoate, sodium 3,4,5-trimethoxybenzoate, sodium 4-methoxybenzoate, sodium 4-dimethylaminobenzoate, sodium 2,6-dihydroxybenzoate, sodium 4-hydroxybenzoate, sodium 4-aminobenzoate, sodium 2,4,6-trimethylbenzoate, sodium 4-t-butylbenzoate, sodium benzoate, lithium 2,6-dimethoxybenzoate, potassium 2,6-dimethoxybenzoate, Cesium 2,6-Dimethoxybenzoate, Magnesium 2,6-Dimethoxybenzoate, Calcium 2,6-Dimethoxybenzoate, Barium 2,6-Dimethoxybenzoate, Sodium 2-Methoxybenzoate,

[0506] The carboxylic acid derivatives of AH1 to AH18 and ANa7, ALi7, AK7, ACs7, and ABu4N7 described in Chemical European Journal, 2005, 11, 1086-1092, J. Legros et al. (including benzoic acid derivatives) are, but are not limited to, these.

[0507] (Method for preparing sulfoxide derivatives)

[0508] A monosulfoxide derivative of formula (B) can be prepared by adding an oxidizing agent dropwise to a solution containing a sulfide derivative of formula (A) and a metal catalyst. However, as long as the reaction proceeds, the order of adding raw materials, reagents, solvents, etc. can be appropriately selected and adjusted by a person skilled in the art.

[0509] (menstruum)

[0510] The solvent in the reaction of the present invention may be any solvent as long as the reaction proceeds. However, from the perspective of facilitating the smooth progress of the reaction, it is preferable to carry out the reaction of the present invention in the presence of a solvent. Furthermore, a solvent in which the solubility of the compound of Formula (A) is high and the solubility of the compound of Formula (B) is low is preferred. In other words, a solvent in which the solubility of the compound of Formula (A) is higher than the solubility of the compound of Formula (B) is preferred.

[0511] As for the type of solvent in the reaction of the present invention, for example,

[0512] water,

[0513] Halogenated aliphatic hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane, trichloroethane, trichloroethylene, tetrachloroethane, tetrachloroethylene, pentachloroethane, etc., preferably dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, more preferably dichloromethane)

[0514] Aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, chlorotoluene, benzotrifluoride, 4-chlorobenzotrifluoride, difluorobenzene, bromobenzene, nitrobenzene, etc., preferably toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene),

[0515] Nitriles (e.g., acetonitrile, propionitrile, butyronitrile, etc., preferably acetonitrile),

[0516] Carboxylic acid esters (e.g., ethyl acetate, isopropyl acetate, butyl acetate, etc.),

[0517] Amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, N-methylpyrrolidone (NMP), etc., preferably N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), more preferably N,N-dimethylformamide (DMF)),

[0518] Alkyl ureas (e.g., N,N'-dimethylimidazolidinone (DMI), etc.),

[0519] Sulfonates (e.g., sulfolan, etc.),

[0520] Carbonate esters (e.g., ethylene carbonate, propylene carbonate, etc.)

[0521] Alcohols (e.g., C1-C6 aliphatic alcohols such as methanol, ethanol, propanol (i.e., 1-propanol), 2-propanol, n-butanol, s-butanol, i-butanol, t-butanol, pentanol (i.e., 1-pentanol), s-amyl alcohol, isoamyl alcohol, t-amyl alcohol, hexanol (i.e., 1-hexanol), cyclohexanol, ethylene glycol, etc., preferably C1-C5 aliphatic alcohols such as methanol, ethanol, propanol, 2-propanol, n-butanol, s-butanol, i-butanol, t-butanol, pentanol, s-amyl alcohol, isoamyl alcohol, t-amyl alcohol, ethylene glycol, etc.), more preferably methanol, ethanol, propanol, 2-propanol, butanol, s-butanol, i-butanol, C1-C4 aliphatic alcohols such as t-butanol and ethylene glycol),

[0522] Ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether, dibutyl ether, di-tert-butyl ether, cyclopentylmethyl ether (CPME), methyl-tert-butyl ether (MTBE), tert-amylmethyl ether (TAME), 1,2-dimethoxyethane (DME), diglyme, triglyme, 4-methoxybenzene, diphenyl ether, etc.), and

[0523] It includes any combination of them in any ratio, but is not limited to these.

[0524] However, in one embodiment, it is preferable to include alcohols. In another embodiment, it is preferable to include nitriles. In yet another embodiment, it is preferable to include alcohols or / and nitriles. These may be applied to any of the following “preferred example of solvent,” “more preferred example of solvent,” “more preferred example of solvent,” “preferred specific example of solvent,” “more preferred specific example of solvent,” and “more preferred specific example of solvent.”

[0525] "2-Propanol" is also called "isopropyl alcohol" or "isopropanol".

[0526] "t-butanol" is also called "tert-butanol" or "tert-butyl alcohol".

[0527] Preferred examples of solvents in terms of reactivity and economic efficiency include water, halogenated aliphatic hydrocarbons, aromatic hydrocarbon derivatives, nitriles, carboxylic acid esters, amides, alcohols, and any combination thereof in any proportion.

[0528] More preferred examples of solvents include water, nitriles, amides, alcohols, and any combination of them in any proportion.

[0529] More preferred examples of solvents include water, nitriles, alcohols, and any combination of them in any proportion.

[0530] Particularly desirable examples of solvents include water, alcohols, and any combination of them in any proportion.

[0531] Preferred embodiments of the solvent include water, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, acetonitrile, ethyl acetate, isopropyl acetate, butyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), methanol, ethanol, propanol, 2-propanol, butanol, t-butanol, t-amyl alcohol, and any combination thereof in any proportion.

[0532] More preferred embodiments of the solvent include water, acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, propanol, 2-propanol, butanol, t-butanol, t-amyl alcohol, and any combination thereof in any proportion.

[0533] More preferred embodiments of the solvent include water, acetonitrile, methanol, ethanol, propanol, 2-propanol, butanol, t-butanol, t-amyl alcohol, and any combination thereof in any proportion.

[0534] In one embodiment, a more preferred embodiment of the solvent comprises water, 2-propanol, t-butanol, and any combination of them in any proportion.

[0535] In another embodiment, more preferred embodiments of the solvent include water, t-butanol, t-amyl alcohol, and any combination thereof in any proportion. Among these, a t-butanol solvent, a t-amyl alcohol solvent, a mixed solvent of t-butanol and water, or a mixed solvent of t-amyl alcohol and water is more preferred. In the present invention, it has been found that, from the perspective of safety, among alcohols, tertiary alcohols such as t-butanol and t-amyl alcohol are preferred as solvents. From the perspective of cost, economic efficiency, etc., a t-butanol solvent or a mixed solvent of t-butanol and water is more preferred. From the perspective of ease of handling, it has been found that a mixed solvent of t-butanol and water is more preferred.

[0536] In another embodiment, from the perspective of the above, a mixed solvent of t-butanol and water, or a mixed solvent of t-amyl alcohol and water is preferred, and a mixed solvent of t-butanol and water is particularly preferred.

[0537] The amount of solvent used may be any amount as long as the reaction proceeds. For the sake of improving yield, suppressing by-products, and economic efficiency, the amount of solvent used may be, for example, 0.01 to 10.0 L (liters), preferably 0.1 to 5.0 L, more preferably 0.3 to 2.0 L, even more preferably 0.4 to 1.5 L, even more preferably 0.4 to 1.2 L, even more preferably 0.5 to 1.2 L, and even more preferably 0.5 to 1.0 L per mole of the sulfide derivative (raw material compound) of Formula (A). However, the amount of solvent used in the reaction of the present invention can be appropriately adjusted by a person skilled in the art. When using a combination of two or more solvents, the ratio of the two or more solvents may be any ratio as long as the reaction proceeds.

[0538] However, in terms of yield, suppression of by-products, and economic efficiency, in one embodiment, the amount of water solvent in the total solvent composed of a solvent other than water and a water solvent is, for example, 0 vol% to 100 vol%, preferably 0 vol% to 30 vol%, more preferably 0 vol% to 20 vol%, and even more preferably 0 vol% to 15 vol% with respect to the total amount of solvent (100 vol%). In another embodiment, the amount of water solvent in the total solvent composed of a solvent other than water and a water solvent is, for example, 5 vol% to 100 vol%, preferably 5 vol% to 30 vol%, more preferably 5 vol% to 20 vol%, and even more preferably 5 vol% to 15 vol% with respect to the total amount of solvent (100 vol%).

[0539] Solvents other than water include, for example, alcohols (e.g., methanol, 2-propanol, t-butanol, t-amyl alcohol) and nitriles (e.g., acetonitrile), but are not limited to these.

[0540] (Solubility)

[0541] From the perspective of ease of operation, the solubility of the compound in the solvent is preferably such that the target product, formula (B), is not dissolved and precipitates, but is not limited thereto.

[0542] As for the solubility of the compound in the reaction solvent of the present invention, for example, in the range of 15°C to 20°C, the solubility of the compound of formula (B), which is the target product, may preferably be 5 to 75 weight%, more preferably 10 to 60 weight%, even more preferably 20 to 55 weight%, and particularly preferably 30 to 40 weight%.

[0543] In addition, for the sake of smooth progress of the reaction, it is preferable that the compound of formula (A), which is the raw material, be dissolved in a solvent. The solubility of the compound of formula (A), which is the raw material, in the range of 15°C to 20°C may be, for example, preferably 5 to 75 weight%, more preferably 10 to 55 weight%, and particularly preferably 30 to 40 weight%.

[0544] In one embodiment, for example, it was found that the solubility of the compound of formula (Ba) in 2-propanol is 30 to 40 wt% in the range of 15°C to 20°C. In another embodiment, from the perspective of crystallization and filtration, it was found that the solubility of the compound of formula (Ba) in a 70 wt% t-butanol / water mixed solution is 4 to 6 wt% in the range of 15°C to 20°C and also about 2 wt% at 5°C.

[0545] (density)

[0546] From the perspective of smooth reaction progress and easy operation, the concentration of the compound of formula (A) at the start of the reaction may be, for example, 5 to 75 weight%, more preferably 20 to 60 weight%, and particularly preferably 35 to 50 weight%. The concentration of the compound of formula (A) is the concentration relative to the entire reaction system.

[0547] (Reaction temperature)

[0548] The reaction temperature of the present invention is not particularly limited. In one aspect, from the viewpoint of improving yield, suppressing by-products, and economic efficiency, the reaction temperature is, for example,

[0549] -10℃ to 60℃ (i.e., minus 10℃ to plus 60℃),

[0550] Preferably 0°C to 60°C (i.e., zero°C to plus 60°C),

[0551] More preferably 5°C to 40°C (i.e., plus 5°C to plus 40°C),

[0552] More preferably 10°C to 35°C (i.e., plus 10°C to plus 35°C),

[0553] More preferably, the range may be 10°C to 20°C (i.e., plus 10°C to plus 20°C). In another embodiment, in the same view as above, the reaction temperature is, for example,

[0554] -20℃ to 50℃ (i.e., minus 20℃ to plus 50℃),

[0555] Preferably -10℃ to 40℃ (i.e., minus 10℃ to plus 40℃),

[0556] More preferably -5°C to 35°C (i.e., minus 5°C to plus 35°C),

[0557] More preferably 15°C to 35°C (i.e., plus 15°C to plus 30°C),

[0558] More preferably, the range may be from 25°C to 35°C (i.e., plus 25°C to plus 35°C). In another embodiment, in the same view as above, the reaction temperature is, for example,

[0559] -10℃ to 60℃ (i.e., minus 10℃ to plus 60℃),

[0560] Preferably -10℃ to 50℃ (i.e., minus 10℃ to plus 50℃),

[0561] More preferably 0°C to 50°C (i.e., zero°C to 50°C),

[0562] More preferably, it may be in the range of 0°C to 40°C (i.e., zero°C to 40°C).

[0563] (Reaction time)

[0564] The reaction time of the present invention is not particularly limited. The lower limit of the reaction time may be, for example, 2 hours or more, preferably 3 hours or more, more preferably 6 hours or more, but is not limited thereto. The upper limit of the reaction time may be, for example, 48 hours or less, preferably 24 hours or less, more preferably 12 hours or less, but is not limited thereto. The range of the reaction time in the present invention can be appropriately adjusted by a person skilled in the art by combining the upper and lower limits mentioned above. The combination of the upper and lower limits of the reaction time may be, for example, 2 hours to 48 hours, preferably 2 hours to 24 hours, more preferably 3 hours to 12 hours, but is not limited thereto. However, the reaction time of the present invention can be appropriately adjusted by a person skilled in the art.

[0565] "Reaction time" refers to the time from the start of adding hydrogen peroxide until the end of the reaction. In the present invention, the reaction time is an aging period for the unreacted raw material to be consumed. In the present invention, the reaction time is preferably equal to the time of adding hydrogen peroxide, but the present invention is not limited thereto. In the present invention, the raw material is consumed immediately after adding hydrogen peroxide, and the hydrogen peroxide does not accumulate in the reaction mixture. Therefore, the present invention is a safe and industrial manufacturing method.

[0566] (Rate of hydrogen peroxide addition)

[0567] It is preferable that the addition rate of hydrogen peroxide be 0.5 mol / hour or less per 1 mol of the compound of formula (A). If the addition rate is 0.5 mol / hour or less, hydrogen peroxide is not accumulated in the reaction mixture. The upper limit of the addition rate may be, for example, 0.5 mol / hour or less, 0.4 mol / hour or less, and 0.3 mol / hour or less.

[0568] In addition, from the perspective of suppressing by-products and economic efficiency, the lower limit of the addition rate may be, for example, 0.05 mol / hour or more, 0.1 mol / hour or more, and 0.2 mol / hour or more.

[0569] The range of the addition rate in the present invention can be appropriately adjusted by a person skilled in the art by combining the upper and lower limits above. The combination of the upper and lower limits of the addition rate may be, for example, 0.05 to 0.5 mol / hour and 0.1 to 0.5 mol / hour. However, the present invention is not limited at all by these combinations.

[0570] (Post-processing; isolation and / or purification)

[0571] The compound of formula (B) which is the target product, in particular 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (Ba), 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, filtration, crystal washing and / or other operations) and improved methods thereof, and any combination thereof.

[0572] In the post-treatment, crystallization of the object including recrystallization and washing of the crystals may be performed. Crystallization of the object including recrystallization may be performed by conventional methods known to those skilled in the art. For example, a non-solvent may be added to a dual-solvent solution of the object. As another example, a saturated solution of the object may be cooled.

[0573] In any of the above cases, the seed may be used.

[0574] For the crystal washing operation, the crystals obtained by filtration may be washed with a solvent. Alternatively, the crystal suspension (slurry) may be stirred and then filtered.

[0575] In addition, from the perspective of yield, purity, and economic efficiency, the filtration temperature may be, for example, in the range of 0°C (zero°C) to 30°C, preferably 0°C (zero°C) to 20°C, more preferably 5°C to 15°C.

[0576] In any of the above cases (crystallization operations including recrystallization, filtration operations, crystal washing tanks, etc.), solvents such as organic solvents (including water-miscible organic solvents) and water are used. Examples of water-miscible organic solvents include, but are not limited to, the following: nitriles (e.g., acetonitrile), alcohols (e.g., methanol, ethanol, 2-propanol, t-butanol), 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.), and combinations thereof, preferably acetonitrile, methanol, ethanol, 2-propanol, t-butanol, acetone and combinations thereof, more preferably acetonitrile, methanol, ethanol, 2-propanol, t-butanol and combinations thereof, more preferably 2-propanol or t-butanol.

[0577] The amounts of organic solvents, such as water-miscible organic solvents, and water may be in any ratio as long as the purpose is achieved. When using a combination of water-miscible organic solvents and water, their ratio may be in any ratio as long as the purpose is achieved. When using a combination of two or more solvents, such as water-miscible organic solvents, their ratio may be in any ratio as long as the purpose is achieved. Their amounts and ratios may be appropriately adjusted by a person skilled in the art according to the purpose and circumstances.

[0578] In any of the above operations (extraction operation, washing operation, crystallization operation including recrystallization, filtration operation, crystal washing tank, etc.), the temperature can be appropriately adjusted by a person skilled in the art. However, from the perspective of yield, purity, economic efficiency, etc., the temperature is, for example, 0°C (zero°C) to 100°C, preferably 0°C to 50°C, more preferably 0°C to 35°C, and even more preferably 5°C to 35°C. Heating and cooling should be performed within these temperature ranges.

[0579] In any of the above operations (extraction operation, washing operation, crystallization operation including recrystallization, filtration operation, crystal washing tank, etc.), the amount of organic solvent (including water-miscible organic solvent) and / or water can be appropriately adjusted by a person skilled in the art by adding and removing them. In addition, in some cases, the solvent may be recovered and recycled. For example, the solvent used in the reaction may be recovered and recycled, and the solvent used in post-treatment (isolation and / or purification) may be recovered and recycled.

[0580] Post-processing (isolation and / or purification) may be performed by appropriately combining all or part of the above operations. In some cases, the above operations may be repeated to suit the purpose of isolation and / or purification. Additionally, a person skilled in the art may appropriately select any combination of the above operations and their order.

[0581] However, in the present invention, the compound of formula (B), which is the target product, particularly 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (Ba), has a solubility of 30% to 40% in an alcohol solvent in the range of 15 to 20°C, so that crystals of the target product precipitate at the end of the reaction. By doing so, it is possible to simply purify the target product by filtration alone. By doing so, the target product with a low melting point can be crystallized from the reaction mixture, and the compound of formula (B), which is the target product, can be manufactured industrially efficiently with high purity by filtration alone.

[0582] (Reaction yield and yield)

[0583] In this specification, the terms “reaction yield” and “yield” each have the following meanings.

[0584] (Reaction yield)

[0585] In the present invention, the reaction yield was determined by analyzing the organic layer of the reaction mixture under the following HPLC analysis conditions (A) or GC analysis conditions. In this specification, the reaction yield is expressed as the percentage of the HPLC area of ​​the target compound.

[0586] The reaction yield in the present invention may be, for example, in the range of 80 to 100%, preferably 85 to 100%, more preferably 90 to 100%, and even more preferably 95 to 100%.

[0587] (transference number)

[0588] In the present invention, the yield can be calculated from the number of moles of the obtained monosulfoxide compound of formula (B) (target compound) relative to the number of moles of the sulfide derivative of formula (A) (raw material compound). That is, the yield in the present invention is expressed by the following formula:

[0589] Yield (%) = (Moles of target compound obtained) / (Moles of raw compound) × 100

[0590] The yield in the present invention may be in the range of, for example, 85 to 100%, preferably 90 to 100%.

[0591] The present invention will be explained in more detail below by way of examples, but the present invention is not limited in any way by these examples.

[0592] In this specification, the following equipment and conditions were used to measure each physical property and yield of the examples and comparative examples.

[0593] (GC: Gas Chromatography)

[0594] Device: GC-2030 (Manufactured by Shimazu Seisakusho, Kabushiki Kaisha)

[0595] Column: DB-17(Agilent J&W)

[0596] Detection temperature: 280℃

[0597] Inlet temperature: 280℃

[0598] Total flow rate: 34 mL / min

[0599] Split ratio: 1:30

[0600] Injection volume: 1 μL

[0601] Oven temperature:

[0602]

[0603] Regarding GC analysis methods, the following literature may be referred to as needed.

[0604] The Japan Chemical Society (ed.), "New Experimental Chemistry Lectures 9: Analytical Chemistry II," pp. 60–86 (1977), Publisher Shingo Iizumi, Maruzen Co., Ltd.

[0605] The Japan Chemical Society (ed.), "Experimental Chemistry Lectures 20-1: Analytical Chemistry," 5th edition, pp. 121–129 (2007), Publisher Seishiro Murata, Maruzen Co., Ltd.

[0606] (HPLC: High-speed liquid chromatography)

[0607] (HPLC analysis conditions)

[0608] Device: LC-20

[0609] Pump: LC-20AT (Manufactured by Shimazu Seisakusho, Kabushiki Kaisha)

[0610] Detector: SPD-20A (Manufactured by Shimazu Seisakusho Co., Ltd.)

[0611] Column: CERI L-column ODS (4.6 x 250 mm), L-C18, 5 μm, 12 nm

[0612] Eluent:

[0613]

[0614] Flow rate: 1.0 mL / min

[0615] Detection: UV 228 nm

[0616] Column temperature: 40℃

[0617] As described above, in evaluating the reaction yield, the area percentage based on the HPLC analysis conditions or GC analysis conditions was used.

[0618] Regarding HPLC analysis methods, the following literature may be referenced as necessary.

[0619] The Japan Chemical Society (ed.), "New Experimental Chemistry Lectures 9: Analytical Chemistry II," pp. 86–112 (1977), Publisher Shingo Iizumi, Maruzen Co., Ltd.

[0620] The Japan Chemical Society (ed.), "Experimental Chemistry Lectures 20-1: Analytical Chemistry," 5th edition, pp. 130–151 (2007), Publisher Seishiro Murata, Maruzen Co., Ltd.

[0621] ( 1 H-NMR: 1 H Nuclear Magnetic Resonance Spectrum; Analysis Conditions)

[0622] Device: JEOL JMN-ECS-300 or JEOL JMN-Lambda-400 (manufactured by JEOL RESONANCE Co., Ltd.)

[0623] Internal reference substance: Tetramethylsilane (TMS)

[0624] (Method for measuring melting point)

[0625] Measurements were taken using a Differential Scanning Calorimeter (DSC). Differential scanning calorimetry analysis was performed using the DSC-60 model (manufactured by Shimadzu Seisakusho, Inc.) at a heating rate of 10°C / min within a temperature range of 0 to 400°C. Regarding the differential scanning calorimetry measurement method, the following literature may be referenced as necessary: ​​The Japan Chemical Society (ed.), "Experimental Chemistry Lectures, 4th Edition: Heat, Pressure," pp. 57–93 (1992), published by Kumao Ebihara, Maruzen Co., Ltd.

[0626] The Japan Chemical Society (ed.), "Experimental Chemistry Lectures, 5th Edition 6: Temperature, Heat, and Pressure," pp. 203–205 (2005), Publisher Seishiro Murata, Maruzen Co., Ltd.

[0627] In the embodiments and comparative examples of the present invention, reaction vessels commonly used by those skilled in the art were used for the preparation of the catalyst solution and the manufacture of the title compound. For example, in Comparative Example 11, an approximately 6 mL screw vial (vial with a screw cap) with an inner diameter of 15 mm and a height of 40 mm was used, equipped with a magnetic stirrer having a cross-shaped magnetic stirrer with an outer diameter (length) of 10 mm and a height (thickness) of 5 mm and a constant temperature bath.

[0628] (Powder X-ray diffraction measurement)

[0629] Device: Rigaku MultiFlex

[0630] X-ray: Cu-Kα

[0631] Measurement method: reflection mode

[0632] Voltage: 40 kV

[0633] Current: 40 mA

[0634] Measurement range: 5 to 80°

[0635] Measurement interval: 0.02°

[0636] In this specification, room temperature is typically in the range of 10°C to 35°C.

[0637] In this specification, "aging" includes stirring a mixture by conventional methods known to those skilled in the art.

[0638] Example 1

[0639] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0640] [Chemical Formula 12]

[0641]

[0642] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (14.96 g, purity 87%, 30 mmol, 100 mol%) and vanadyl acetylacetonate (79.5 mg, 0.3 mmol, 1 mol%) were added to 2-propanol (24 mL, 0.8 L / mol). The mixture was stirred for 30 minutes at a temperature of 15 to 20°C. Thereupon, 35% hydrogen peroxide (3.5 g, 36 mmol, 120 mol%) was added dropwise over 3 hours at a temperature of 15 to 20°C, and the mixture was aged for 1 hour while maintaining a temperature of 15 to 20°C.

[0643] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0644] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 95.5%,

[0645] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.5%,

[0646] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.9%.

[0647] The reaction mixture was an orange-brown suspension at 15°C. Crystals of the target product precipitated. A 2.5% aqueous sodium sulfite solution (24.6 g, 6 mmol, 20 mol%) was added to the reaction mixture, and the mixture was stirred at 5°C for 1 hour. The resulting crude product was filtered and fractionated at 5°C. The obtained crystals were sequentially washed with a mixed solution of 12 mL (0.4 L / mol) 2-propanol and 12 mL (0.4 L / mol) water, followed by 24 mL (0.8 L / mol) water. As a result, white crystals of the target product (compound Ba) were obtained with a yield of 90.5% (12.73 g, purity 95.2%).

[0648] 1 H-NMR (300 MHz, CDCl3) δ (ppm, based on TMS): 1.57-1.66 (m, 2H), 1.74-1.93 (m, 4H), 2.92 (t, 2H), 3.30-3.43 (m, 1H), 3.66-3.78 (m, 1H), 4.13 (t, 2H), 7.21(d, 1H), 7.54(d, 1H)

[0649] Melting point: 43℃

[0650] This was an industrially excellent manufacturing method in which a high-purity product could be obtained by crystallizing a product with a low melting point from a reaction mixture and filtering it.

[0651] Example 2

[0652] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0653] [Chemical Formula 13]

[0654]

[0655] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (9.78 g, purity 88%, 20 mmol, 100 mol%) and vanadyl acetylacetonate (53 mg, 0.2 mmol, 1 mol%) were added to 2-propanol (20 mL, 1.0 L / mol). The mixture was stirred for 30 minutes at a temperature of 15 to 20°C. Thereupon, 33% hydrogen peroxide (3.09 g, 30 mmol, 150 mol%) was added dropwise over 3 hours at a temperature of 15 to 20°C, and the mixture was aged for 1 hour while maintaining a temperature of 15 to 20°C.

[0656] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0657] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 94.0%,

[0658] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.2%,

[0659] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.9%.

[0660] The reaction mixture was an orange-brown suspension at 15°C. Crystals of the target product precipitated. A 13.3% aqueous sodium sulfite solution (8.5 g, 10 mmol, 0.5 mol%) was added to the reaction mixture, and the mixture was stirred at 5°C for 1 hour. The resulting crude product was filtered and fractionated at 5°C. The obtained crystals were sequentially washed with a mixed solution of 5 mL (0.4 L / mol) 2-propanol and 9 mL (0.4 L / mol) water, followed by 20 mL (0.8 L / mol) water. As a result, white crystals of the target product (compound Ba) were obtained with a yield of 94.5% (8.73 g, purity 96.7%).

[0661] Example 3

[0662] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0663] [Chemical Formula 14]

[0664]

[0665] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (9.78 g, purity 88%, 20 mmol, 100 mol%) and vanadyl acetylacetonate (53 mg, 0.2 mmol, 1 mol%) were added to 2-propanol (10 mL, 0.5 L / mol). The mixture was stirred for 30 minutes at a temperature of 15 to 20°C. Thereupon, 33% hydrogen peroxide (3.09 g, 30 mmol, 150 mol%) was added dropwise over 3 hours at a temperature of 15 to 20°C, and the mixture was aged for 1 hour while maintaining a temperature of 15 to 20°C.

[0666] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0667] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 91.4%,

[0668] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 3.5%,

[0669] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.5%.

[0670] Example 4

[0671] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0672] [Chemical Formula 15]

[0673]

[0674] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (9.78 g, purity 88%, 20 mmol, 100 mol%) and vanadyl acetylacetonate (53 mg, 0.2 mmol, 1 mol%) were added to 2-propanol (20 mL, 1.0 L / mol). The mixture was cooled to a temperature of 5°C and stirred for 30 minutes. Then, 33% hydrogen peroxide (3.09 g, 30 mmol, 150 mol%) was added dropwise over 3 hours at a temperature of 5°C, and the mixture was aged for 1 hour while maintaining the temperature at 5°C.

[0675] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0676] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 93.2%,

[0677] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 1.9%,

[0678] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.5%.

[0679] Example 5

[0680] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0681] [Chemical Formula 16]

[0682]

[0683] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87%, 5 mmol, 100 mol%) and vanadyl acetylacetonate (26.5 mg, 0.1 mmol, 2 mol%) were added to methanol (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 24 hours.

[0684] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0685] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 94.8%,

[0686] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.6%,

[0687] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.9%.

[0688] Example 6

[0689] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0690] [Chemical Formula 17]

[0691]

[0692] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87%, 5 mmol, 100 mol%) and vanadium(III) acetylacetonate (34.8 mg, 0.1 mmol, 2 mol%) were added to methanol (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 24 hours.

[0693] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0694] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 95.5%,

[0695] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.8%,

[0696] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4%.

[0697] Example 7

[0698] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0699] [Chemical Formula 18]

[0700]

[0701] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87%, 5 mmol, 100 mol%) and vanadium(III) acetylacetonate (34.8 mg, 0.1 mmol, 2 mol%) were added to acetonitrile (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 24 hours.

[0702] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0703] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 85.6%,

[0704] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 8.4%,

[0705] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.3%.

[0706] Example 8

[0707] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0708] [Chemical Formula 19]

[0709]

[0710] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.29 g, purity 93%, 5 mmol, 100 mol%) and titanyl(IV) acetylacetonate (26.2 mg, 0.1 mmol, 2 mol%) were added to methanol (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 63 hours.

[0711] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0712] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 87.2%,

[0713] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 2.0%,

[0714] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 5.2%.

[0715] Example 9

[0716] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0717] [Chemical Formula 20]

[0718]

[0719] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87%, 5 mmol, 100 mol%) and ammonium molybdate tetrahydrate (8.7 mg, 0.007 mmol, 0.14 mol%, 1 mol% as molybdenum atoms) were added to 2-propanol (4 mL, 0.8 L / mol). The mixture was cooled to a temperature of 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at a temperature of 0°C for 30 minutes, and then aged at room temperature for 17 hours.

[0720] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0721] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 95.6%,

[0722] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.5%,

[0723] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.2%.

[0724] The reaction mixture was a yellow suspension at 25°C. Crystals of the target product precipitated.

[0725] Example 10

[0726] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0727] [Chemical Formula 21]

[0728]

[0729] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.15 g, purity 94%, 5 mmol, 100 mol%) and ammonium molybdate tetrahydrate (8.7 mg, 0.007 mmol, 0.14 mol%, 1 mol% as molybdenum atoms) were added to acetonitrile (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 24 hours.

[0730] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0731] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 87.6%,

[0732] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.3%,

[0733] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 7.0%.

[0734] Example 11

[0735] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0736] [Chemical Formula 22]

[0737]

[0738] In a 250 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (33.1 g, purity 88%, 80 mmol, 100 mol%) and vanadyl acetylacetonate (212.1 mg, 0.8 mmol, 1 mol%) were added to t-butanol (60 mL, 0.8 L / mol). The mixture was stirred for 30 minutes at a temperature of 25°C. Thereupon, 35% hydrogen peroxide (9.3 g, 96 mmol, 120 mol%) was added dropwise over 3 hours at a temperature of 25°C, and the mixture was aged for 1 hour while maintaining the temperature at 25°C.

[0739] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0740] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 96.1%,

[0741] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.2%,

[0742] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4%.

[0743] The reaction mixture was an orange-brown solution at 25°C. t-butanol (8 mL, 0.1 L / mol) and a 2% aqueous sodium bisulfite solution (40.8 g, 8 mmol, 10 mol%) were added to the reaction mixture, and the mixture was stirred at 20°C for 1 hour. The resulting crude product was filtered and fractionated at 20°C. The obtained crystals were sequentially washed with a mixed solution of 20 mL (0.3 L / mol) 2-propanol and 36 mL (0.5 L / mol) water, followed by 24 mL (0.3 L / mol) water. As a result, white crystals of the target product (compound Ba) were obtained with a yield of 85.1% (31.5 g, purity 96.6%).

[0744] Example 12

[0745] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0746] [Chemical Formula 23]

[0747]

[0748] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.2 g, purity 88%, 25 mmol, 100 mol%) and vanadyl acetylacetonate (66.3 mg, 0.25 mmol, 1 mol%) were added to t-butanol (19 mL, 0.8 L / mol). The mixture was stirred for 30 minutes at a temperature of 40°C. Then, 35% hydrogen peroxide (2.9 g, 30 mmol, 120 mol%) was added dropwise over 3 hours at a temperature of 40°C, and the mixture was aged for 1 hour while maintaining the temperature at 40°C.

[0749] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0750] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 94.6%,

[0751] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.7%,

[0752] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4%.

[0753] A 9.4% aqueous sodium bisulfite solution (2.8 g, 2.5 mmol, 10 mol%) and 10 mL of water (0.4 L / mol) were added to the reaction mixture, and the mixture was stirred at 20°C for 1 hour. The resulting crude product was filtered and fractionated at 20°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL of 2-propanol (0.3 L / mol) and 11 mL of water (0.5 L / mol), followed by 8 mL of water (0.3 L / mol). As a result, white crystals of the target product (compound Ba) were obtained with a yield of 86.2% (9.9 g, purity 96.9%).

[0754] Example 13

[0755] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0756] [Chemical Formula 24]

[0757]

[0758] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.2 g, purity 88%, 25 mmol, 100 mol%) and vanadyl acetylacetonate (66.3 mg, 0.25 mmol, 1 mol%) were added to t-butanol (19 mL, 0.8 L / mol). The mixture was stirred for 30 minutes at a temperature of 30°C. Then, 35% hydrogen peroxide (2.9 g, 30 mmol, 120 mol%) was added dropwise over 3 hours at a temperature of 30°C, and the mixture was aged for 1 hour while maintaining the temperature at 30°C.

[0759] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0760] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 95.1%,

[0761] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0%,

[0762] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.9%.

[0763] A 2% aqueous sodium bisulfite solution (12.8 g, 2.5 mmol, 10 mol%) was added to the reaction mixture, and the mixture was stirred at a temperature of 15°C for 1 hour. The resulting crude product was filtered and fractionated at 15°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL (0.3 L / mol) 2-propanol and 11 mL (0.5 L / mol) water, followed by 8 mL (0.3 L / mol) water. As a result, white crystals of the target product (compound Ba) were obtained with a yield of 84.4% (9.69 g, purity 97.3%).

[0764] Example 14

[0765] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0766] [Chemical Formula 25]

[0767]

[0768] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.2 g, purity 88%, 25 mmol, 100 mol%) and vanadyl acetylacetonate (33.2 mg, 0.13 mmol, 0.5 mol%) were added to t-butanol (19 mL, 0.8 L / mol). The mixture was stirred for 30 minutes at a temperature of 30°C. Thereupon, 35% hydrogen peroxide (2.9 g, 30 mmol, 120 mol%) was added dropwise over 3 hours at a temperature of 30°C, and the mixture was aged for 1 hour while maintaining a temperature of 30°C.

[0769] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0770] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 96.6%,

[0771] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.6%,

[0772] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4%.

[0773] A 2% aqueous sodium bisulfite solution (12.8 g, 2.5 mmol, 10 mol%) was added to the reaction mixture, and the mixture was stirred at a temperature of 15°C for 1 hour. The resulting crude product was filtered and fractionated at 15°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL (0.3 L / mol) 2-propanol and 11 mL (0.5 L / mol) water, followed by 8 mL (0.3 L / mol) water. As a result, white crystals of the target product (compound Ba) were obtained with a yield of 87.3% (9.84 g, purity 99.1%).

[0774] Example 15

[0775] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0776] [Chemical Formula 26]

[0777]

[0778] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.2 g, purity 88%, 25 mmol, 100 mol%) and vanadyl acetylacetonate (66.4 mg, 0.25 mmol, 1 mol%) were added to t-butanol (13 mL, 0.5 L / mol). The mixture was stirred for 30 minutes at a temperature of 30°C. Thereupon, 35% hydrogen peroxide (2.9 g, 30 mmol, 120 mol%) was added dropwise over 3 hours at a temperature of 30°C, and the mixture was aged for 2 hours while maintaining a temperature of 30°C. In addition, 35% hydrogen peroxide (0.24 g, 2.5 mmol, 10 mol%) was added at a temperature of 30°C, and the mixture was aged for 30 minutes while maintaining the temperature at 30°C.

[0779] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0780] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 94.6%,

[0781] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.6%,

[0782] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.3%.

[0783] Example 16

[0784] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0785] [Chemical Formula 27]

[0786]

[0787] In a 250 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (44.0 g, purity 88%, 90 mmol, 100 mol%) and vanadyl acetylacetonate (239 mg, 0.9 mmol, 1 mol%) were added to t-butanol (77 mL, 0.9 L / mol) and water (6 mL, 0.1 L / mol). The mixture was stirred for 30 minutes at a temperature of 30°C. Thereupon, 34% hydrogen peroxide (11 g, 108 mmol, 120 mol%) was added dropwise over 3 hours at a temperature of 30°C, and the mixture was aged for 1 hour while maintaining a temperature of 30°C.

[0788] The reaction mixture was analyzed by GC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0789] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 96.8%,

[0790] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.5%,

[0791] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.9%.

[0792] The reaction mixture was an orange-brown solution at 30°C. A 9.4% aqueous sodium bisulfite solution (9.9 g, 9.0 mmol, 10 mol%) was added to the reaction mixture, and the mixture was stirred at a temperature of 20°C for 30 minutes. Seed crystals were added to the mixture at 20°C, the mixture was cooled to 5°C over a period of 1 hour, and aged for 14 hours. The resulting crude product was filtered and fractionated at 5°C. The obtained crystals were sequentially washed with a mixed solution of 23 mL (0.3 L / mol) t-butanol and 41 mL (0.5 L / mol) water, followed by 27 mL (0.3 L / mol) water. As a result, white crystals of the target product (compound Ba) were obtained with a yield of 88.9% (37.1 g, purity 96.6%).

[0793] As the seed crystal used in the above example, a crystal obtained in the same manner as in Example 1 was used.

[0794] Example 17

[0795] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0796] [Chemical Formula 28]

[0797]

[0798] In a 250 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (38.9 g, purity 89%, 80 mmol, 100 mol%) and vanadyl acetylacetonate (212 mg, 0.8 mmol, 1 mol%) were added to t-butanol (68 mL, 0.9 L / mol) and water (5 mL, 0.1 L / mol). The mixture was stirred for 30 minutes at a temperature of 30°C. Thereupon, 35% hydrogen peroxide (9.3 g, 96 mmol, 120 mol%) was added dropwise over 3 hours at a temperature of 30°C, and the mixture was aged for 1 hour while maintaining the temperature at 30°C.

[0799] The reaction mixture was analyzed by GC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0800] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 97.1%,

[0801] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.6%,

[0802] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 1.4%.

[0803] The reaction mixture was an orange-brown solution at 30°C. A 3.7% aqueous sodium bisulfite solution (22.7 g, 8 mmol, 10 mol%) was added to the reaction mixture, and the mixture was cooled from 30°C to 25°C over 30 minutes. Seed crystals were added to the mixture at 25°C, the mixture was cooled to 5°C over 1 hour, and aged for 2 hours. The resulting crude product was filtered and fractionated at 5°C. The obtained crystals were sequentially washed with a mixed solution of 20 mL (0.3 L / mol) t-butanol and 36 mL (0.5 L / mol) water, followed by 24 mL (0.3 L / mol) water. As a result, white crystals of the target product (compound Ba) were obtained with a yield of 91.5% (33.6 g, purity 97.4%).

[0804] As the seed crystal used in the above example, a crystal obtained in the same manner as in Example 1 was used.

[0805] Example 18

[0806] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0807] [Chemical Formula 29]

[0808]

[0809] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.1 g, purity 88%, 25 mmol, 100 mol%) and vanadyl acetylacetonate (66.4 mg, 0.25 mmol, 1 mol%) were added to t-butanol (19 mL, 0.8 L / mol). The mixture was stirred at a temperature of 30°C for 30 minutes. 35% hydrogen peroxide (1.0 g, 10 mmol, 40 mol%) was added dropwise over 1 hour at a temperature of 30°C, and then 35% hydrogen peroxide (2.0 g, 20 mmol, 80 mol%) was added dropwise over 2 hours while cooling to a temperature of 20°C, and the mixture was aged for 1 hour while maintaining a temperature of 20°C.

[0810] The reaction mixture was analyzed by GC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0811] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 97.6%,

[0812] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.6%,

[0813] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.9%.

[0814] The reaction mixture was an orange-brown suspension at 20°C. Crystals of the target product precipitated. A 5% aqueous sodium bisulfite solution (5.3 g, 2.5 mmol, 10 mol%) and 5 mL of water (0.2 L / mol) were added to the reaction mixture. The mixture was stirred at 15°C for 1 hour. The obtained crystals were filtered and separated at 15°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL of 2-propanol (0.3 L / mol) and 11 mL of water (0.5 L / mol), followed by 8 mL of water (0.3 L / mol). As a result, white crystals of the target product (compound Ba) were obtained with a yield of 86.2% (9.9 g, purity 97.7%).

[0815] Example 19

[0816] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0817] [Chemical Formula 30]

[0818]

[0819] In a 50 mL reaction flask, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (12.1 g, purity 88%, 25 mmol, 100 mol%) and vanadyl acetylacetonate (66.4 mg, 0.25 mmol, 1 mol%) were added to t-amyl alcohol (19 mL, 0.8 L / mol). The mixture was stirred for 30 minutes at a temperature of 17°C. Then, 33.7% hydrogen peroxide (3.0 g, 30 mmol, 120 mol%) was added dropwise over 3 hours at a temperature of 17°C, and the mixture was aged for 1 hour.

[0820] The reaction mixture was analyzed by GC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0821] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 97.4%,

[0822] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 0.7%,

[0823] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.5%.

[0824] The reaction mixture was an orange-brown suspension at 17°C. A 5% aqueous sodium bisulfite solution (5.3 g, 2.5 mmol, 10 mol%) and 15 mL of water (0.6 L / mol) were added to the reaction mixture, and the mixture was stirred for 5 minutes at a temperature of 40°C. The resulting mixture was separated into an organic layer and an aqueous layer. Subsequently, the obtained organic layer was concentrated under reduced pressure and removed by solvent distillation. 2-propanol (19 mL, 0.8 L / mol) and water (5 mL, 0.2 L / mol) were added to the crude product, and the mixture was heated to a temperature of 40°C. It was cooled to a temperature of 10°C over 2 hours and aged for 1 hour. The obtained crystals were filtered and fractionated at 10°C. The obtained crystals were sequentially washed with a mixed solution of 6 mL (0.3 L / mol) of 2-propanol and 11 mL (0.5 L / mol) of water, followed by 8 mL (0.3 L / mol) of water. As a result, white crystals of the target product (compound Ba) were obtained with a yield of 85.9% (9.9 g, purity 96.6%).

[0825] NMR data of the byproduct disulfoxide derivative is described.

[0826] 1H-NMR (300 MHz, CDCl3) δ (ppm, based on TMS): 1.67-1.79 (m, 2H), 1.90-2.01 (m, 4H), 2.86-2.96 (m, 1H), 3.08-3.17 (m, 1H), 3.33-3.41 (m, 1H), 3.68-3.76(m, 1H), 4.15(t, 2H), 7.23(d, 1H), 7.55(d, 1H)

[0827] R 1 Compounds in which adjacent sulfides are oxidized were not identified in the above examples.

[0828] Comparative Example 1

[0829] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0830] [Chemical Formula 31]

[0831]

[0832] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.60 g, purity 82.7%, 5 mmol, 100 mol%) and manganese(III) acetylacetate (35 mg, 0.1 mmol, 2 mol%) were added to methanol (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 24 hours.

[0833] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0834] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 0%,

[0835] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 93.6%,

[0836] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0837] Comparative Example 2

[0838] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0839] [Chemical Formula 32]

[0840]

[0841] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.30 g, purity 93.9%, 5 mmol, 100 mol%) and iron(III) acetylacetate (17.7 mg, 0.05 mmol, 1 mol%) were added to methanol (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 24 hours.

[0842] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0843] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 0%,

[0844] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 93.6%,

[0845] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0846] Comparative Example 3

[0847] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0848] [Chemical Formula 33]

[0849]

[0850] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87%, 5 mmol, 100 mol%) and zirconium(IV) oxychloride octahydrate (32 mg, 0.1 mmol, 2 mol%) were added to methanol (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 20 hours.

[0851] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0852] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 2.1%,

[0853] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 93.4%,

[0854] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0855] Comparative Example 4

[0856] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0857] [Chemical Formula 34]

[0858]

[0859] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87%, 5 mmol, 100 mol%) and sodium tungstate dihydrate (29.3 mg, 0.1 mmol, 2 mol%) were added to 2-propanol (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 20 hours.

[0860] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0861] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 23.4%,

[0862] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 72.2%,

[0863] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0.1%.

[0864] Comparative Example 5

[0865] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0866] [Chemical Formula 35]

[0867]

[0868] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87%, 5 mmol, 100 mol%) and ammonium paratungstate pentahydrate (13.1 mg, 0.004 mmol, 0.08 mol%, 1 mol% as tungsten atoms) were added to methanol (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 20 hours.

[0869] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0870] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 7.3%,

[0871] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 88.3%,

[0872] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0873] Comparative Example 6

[0874] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0875] [Chemical Formula 36]

[0876]

[0877] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.60 g, purity 82.7%, 5 mmol, 100 mol%) and manganese(III) acetylacetate (35 mg, 0.1 mmol, 2 mol%) were added to acetonitrile (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 24 hours.

[0878] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0879] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 0%,

[0880] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 93.3%,

[0881] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0882] Comparative Example 7

[0883] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0884] [Chemical Formula 37]

[0885]

[0886] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.30 g, purity 93.9%, 5 mmol, 100 mol%) and iron(III) acetylacetate (17.7 mg, 0.05 mmol, 1 mol%) were added to acetonitrile (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 24 hours.

[0887] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0888] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 0.9%,

[0889] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 93.8%,

[0890] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0891] Comparative Example 8

[0892] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0893] [Chemical Formula 38]

[0894]

[0895] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87%, 5 mmol, 100 mol%) and zirconium(IV) oxychloride octahydrate (32 mg, 0.1 mmol, 2 mol%) were added to acetonitrile (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 20 hours.

[0896] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0897] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 1%,

[0898] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 94.4%,

[0899] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0900] Comparative Example 9

[0901] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0902] [Chemical Formula 39]

[0903]

[0904] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (4.7 g, purity 90.4%, 10 mmol, 100 mol%) and sodium tungstate dihydrate (164 mg, 0.5 mmol, 5 mol%) were added to acetonitrile (5 mL, 0.5 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (1.2 g, 12 mmol, 120 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 69 hours.

[0905] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0906] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 26%,

[0907] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 65.8%,

[0908] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0909] Comparative Example 10

[0910] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0911] [Hwahasik 40]

[0912]

[0913] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.47 g, purity 87%, 5 mmol, 100 mol%) and ammonium paratungstate pentahydrate (13.1 mg, 0.004 mmol, 0.08 mol%, 1 mol% as tungsten atoms) were added to acetonitrile (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 20 hours.

[0914] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0915] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 1.5%,

[0916] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 94.1%,

[0917] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0918] Comparative Example 11

[0919] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0920] [Chemical Formula 41]

[0921]

[0922] (1) Preparation of catalyst solution

[0923] Vanadyl acetylacetonate (1.3 mg, 0.005 mmol, 1 mol%), (E)-2-{[(1-hydroxy-2-methylpropane-2-yl)imino]methyl}phenol (ligand of (3-4) described in WO2017 / 150478 (Patent Document 2), 1.0 mg, 0.005 mmol, 1 mol%), sodium 2,6-dimethoxybenzoate (benzoic acid derivative of (4-1) described in WO2017 / 150478 (Patent Document 2), 5.1 mg, 0.025 mmol, 5 mol%), and dichloromethane (1 mL, 0.5 L / mol) were added to a screw-capped vial. The mixture was stirred at room temperature for 30 minutes.

[0924] (2) Preparation of the compound of the title

[0925] 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (244 mg, purity 88.2%, 0.500 mmol, 100 mol%) was dissolved in dichloromethane (1 mL, 0.5 L / mol). The catalyst solution prepared in (1) above was added to it. The mixture was cooled to 0°C. 35% hydrogen peroxide (97.1 mg, 1.0 mmol, 200 mol%) was added to it. The mixture was stirred at 0°C for 15 hours. The organic layer of the reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0926] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 1.2%,

[0927] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 92.3%,

[0928] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0929] Comparative Example 11 was carried out by changing the metal catalyst of WO2017 / 150478 (Patent Document 2) from an iron catalyst to a vanadium catalyst. However, it was difficult to obtain the object (B) of the present invention by changing only the metal catalyst.

[0930] By-products;

[0931] Comparative Example 12

[0932] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0933] [Chemical Formula 42]

[0934]

[0935] In a 30 mL test tube, 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (2.30 g, purity 93.9%, 5 mmol, 100 mol%) and iron(III) acetylacetate (17.7 mg, 0.05 mmol, 1 mol%) were added to dichloromethane (4 mL, 0.8 L / mol). The mixture was cooled to 0°C. Then, 35% hydrogen peroxide (0.728 g, 7.5 mmol, 150 mol%) was added. The mixture was stirred at 0°C for 30 minutes, and then aged at room temperature for 24 hours.

[0936] The reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0937] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 2.3%,

[0938] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 93.2%,

[0939] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0940] Comparative Example 13

[0941] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0942] [Chemical Formula 43]

[0943]

[0944] 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (14.65 g, purity 88%, 30 mmol, 100 mol%), vanadyl acetylacetonate (318 mg, 1.2 mmol, 4 mol%), and chloroform (40 mL, 1.3 L / mol) were added to a 250 mL reaction flask and stirred for 10 minutes at a room temperature of 25 °C. Subsequently, 35% hydrogen peroxide (5.24 g, 54 mmol, 180 mol%) was added dropwise to the mixture over a period of 10 minutes. After aging for 4 hours at a room temperature of 25 °C, the organic layer of the reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0945] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 2.2%,

[0946] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 93.7%,

[0947] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0948] Comparative Example 14

[0949] Preparation of 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether

[0950] [Chemical Formula 44]

[0951]

[0952] 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (14.65 g, purity 88%, 30 mmol, 100 mol%), vanadyl acetylacetonate (318 mg, 1.2 mmol, 4 mol%), and chloroform (40 mL, 1.3 L / mol) were added to a 250 mL reaction flask and stirred for 10 minutes at a temperature of 25°C. Subsequently, (S)-(2,4-di-tert-butyl-6-{(E)-[(1-hydroxy-3,3-dimethylbutane-2-yl)imino]methyl}phenol (600 mg, 1.8 mmol, 6 mol%) was added. After 10 minutes, 35% hydrogen peroxide (5.24 g, 54 mmol, 180 mol%) was added dropwise over 10 minutes. After aging at a temperature of 25°C for 4 hours, the organic layer of the reaction mixture was analyzed by HPLC (area percentage). As a result, the components of the reaction mixture, excluding the solvent, etc., were as follows:

[0953] 5-trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (target compound): 17.5%,

[0954] 5-Trifluoromethylthiopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether (raw material compound): 70.5%,

[0955] 5-trifluoromethylsulfinylpentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylsulfinyl)phenyl]ether (by-product; disulfoxide derivative): 0%.

[0956] Aging was continued for another 20 hours, but the reaction did not change from 4 hours.

[0957] Comparative Examples 13 and 14 were follow-up examples of prior art using a ligand and a vanadium catalyst. In Comparative Example 13, the reaction was carried out without using a ligand, similar to the example of the present invention, in the method of Example 1 of US2011 / 0015405A1 (Japanese Patent No. 2012-532906) (Patent Document 3). It was difficult to obtain the target product (B) of the reaction by merely changing whether or not a ligand was used. In Comparative Example 14, the reaction was carried out in the same way using the same metal catalyst, ligand, oxidizing agent, and solvent as in Example 1 of US2011 / 0015405A1 (Japanese Patent No. 2012-532906) (Patent Document 3). As shown in Comparative Example 14, even when the method of the prior art was applied to the raw material of the present invention, the reaction did not proceed sufficiently. It was confirmed that the prior art cannot be applied to the manufacture of the target product of the present invention.

[0958] Example 20

[0959] White crystals of the compound of formula (Ba) were obtained by the same manufacturing method as in Example 16. Here, the crystals obtained in the same manner as in Example 16 were used as seed crystals. The obtained crystals were vacuum dried. The melting point was 46°C to 50°C. The obtained crystals were subjected to powder X-ray diffraction. The results of the powder X-ray diffraction measurement are shown in Figure 1.

[0960] Example 21

[0961] White crystals of the compound of formula (Ba) were obtained by the same manufacturing method as in Example 16. Here, the crystals obtained in the same manner as in Example 16 were used as seed crystals. The obtained crystals were melted, moisture was removed by vacuum drying, and then cooled. The obtained crystals were ground in a mill. The melting point was 47°C to 48°C. The obtained crystals were subjected to powder X-ray diffraction. The results of the powder X-ray diffraction measurement are shown in Figure 2.

[0962] Example 22

[0963] White crystals of the compound of formula (Ba) were obtained using the same manufacturing method as in Example 1. The obtained crystals were subjected to recrystallization. Here, the recrystallization conditions were the same as those of Example 1 (recrystallization from 2-propanol and water). The obtained crystals were filtered and dried. The melting point was 46°C to 50°C. The obtained crystals were subjected to powder X-ray diffraction. The results of the powder X-ray diffraction measurement are shown in Figure 3.

[0964]

[0965] Reference Preparation Example 1

[0966] Preparation of 4-fluoro2-chlorophenol

[0967] [Chemical Formula 45]

[0968]

[0969] In a 1000 mL reaction flask, 2-fluorophenol (112.1 g, purity 100%, 1000 mmol, 100 mol%), diphenyl sulfide (372.5 mg, 2.000 mmol, 0.2 mol%), and anhydrous iron(III) chloride (162.2 mg, 1.000 mmol, 0.1 mol%) were added to dichloromethane (610 mL, 0.61 L / mol). The mixture was stirred for 30 minutes at a temperature of 5 to 10°C. Chlorine gas (70.9 g, 1000 mmol, 100 mol%) was blown in over 6 hours at a temperature of 5 to 10°C, and the mixture was aged for 1 hour while maintaining the temperature at 5 to 10°C.

[0970] The reaction mixture was a yellow clarified liquid at 10°C. Nitrogen gas was blown into the reaction mixture at 60 mL / min for 2 hours. As a result, a dichloromethane solution of the target product was obtained with a yield of 97% (909.7 g, purity 15.6%).

[0971] 1 H-NMR (300 MHz, CDCl3) δ (ppm, based on TMS): 5.09 (d, 1H), 6.94 (dd, 1H), 7.02 (ddd, 1H), 7.11 (dd, 1H)

[0972] Industrial applicability

[0973] As disclosed in Patent Document 1, the monosulfoxide derivative of Formula (B) has excellent mite-killing activity.

[0974] According to the present invention, a novel method for the industrially desirable production of a monosulfoxide derivative of formula (B) which is useful as a pesticide such as a mite killer is provided.

[0975] As described above in this specification, the method of the present invention is economical, environmentally friendly, and has high industrial utility value.

[0976] In particular, the method of the present invention allows for the selective production of a target monosulfoxide derivative by avoiding excessive oxidation to a disulfoxide derivative. Furthermore, simple operation without the use of ligands is possible.

[0977] Therefore, the present invention has the advantage of not requiring the removal of disulfoxide derivatives, which are by-products that are difficult to remove.

[0978] In short, the present invention has high industrial applicability.

[0979] All publications, patents, and patent applications described herein are incorporated by reference in their entirety for the purpose of explaining and disclosing the methods described in such publications, patents, and patent applications that may be used in connection with the description of this specification. All publications, patents, and patent applications described herein are expressed by reference to the same extent as they are individually incorporated, to the extent necessary to understand or complete the disclosure of the invention. All publications, patents, and patent applications discussed above and throughout this specification are provided only for disclosure prior to the filing date of this application.

[0980] Any method and reagent that is the same or equivalent as described in this specification may be used in the method and practice of the present invention. Accordingly, the present invention is not limited by the above description, but is intended to be defined by the claims and their equivalents. The equivalents fall within the scope of the present invention as defined by the appended claims.

Claims

Claim 1 A method for preparing a compound of formula (B) comprises an oxidation process of reacting a compound of formula (A) with hydrogen peroxide in the presence of a metal catalyst, and (In the food, R 1 is a C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C1-C4 haloalkyl group, C2-C4 haloalkenyl group, or C2-C4 haloalkynyl group; R 2 and R 3 are each independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, or a C2-C4 haloalkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; and n is 5 or 6.) (during food, R 1 , R 2 , R 3 and n is as defined above.) A method in which the metal catalyst is one or more catalysts selected from the group consisting of vanadium catalyst, molybdenum catalyst and titanium catalyst, and ligands and benzoic acid derivatives are not used in the oxidation process. Claim 2 A method according to claim 1, wherein the metal catalyst is a vanadium catalyst. Claim 3 A method according to claim 1, wherein the oxidation process is carried out in a solvent. Claim 4 A method according to claim 3, wherein the solvent is a solvent comprising alcohol. Claim 5 The method of claim 4, wherein the alcohol is a C1-C6 aliphatic alcohol. Claim 6 The method of claim 4, wherein the alcohol is methanol, ethanol, 2-propanol, t-butanol, or t-amyl alcohol. Claim 7 The method of claim 4, wherein the alcohol is methanol, 2-propanol, t-butanol, or t-amyl alcohol. Claim 8 The method of claim 3, wherein the solvent is acetonitrile, methanol, 2-propanol, t-butanol or t-amyl alcohol, or a mixture thereof with water. Claim 9 A method according to any one of claims 1 to 8, comprising a process of recovering crystals of the compound of formula (B) after the oxidation process. Claim 10 A method according to any one of claims 1 to 8, wherein the content of the compound of formula (C) is 10% or less with respect to the weight of the compound of formula (B): (In the food, R 1 is a C1-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C1-C4 haloalkyl group, C2-C4 haloalkenyl group, or C2-C4 haloalkynyl group; R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C1-C4 haloalkyl group, a C2-C4 haloalkenyl group, a C2-C4 haloalkynyl group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group; also, n is 5 or 6.) Claim 11 A method according to any one of claims 1 to 8, wherein the compound of formula (B) is a crystal. Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete

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