Preparation method and intermediate of trifluoroethyl sulfoxide substituted aryl compound

Abstract

The invention relates to the technical field of pesticide acaricides, in particular to a preparation method of a trifluoroethyl sulfoxide substituted aryl compound and an intermediate of the trifluoroethyl sulfoxide substituted aryl compound. According to the preparation method, cheap substituted benzene is taken as an initial raw material, sulfonation, reduction, alkylation and nitration oxidation are carried out to prepare an m-nitro-substituted trifluoroethyl sulfoxide benzene compound, then nitro is reduced into amino, and an intermolecular substitution splicing reaction is carried out to prepare the trifluoroethyl sulfoxide substituted aryl compound with high yield. The preparation method is short in step, simple and convenient to operate, environment-friendly, low in cost, high in yield and more suitable for large-scale industrial production. The invention also relates to the m-nitro-substituted trifluoroethyl sulfoxide benzene compound and a preparation method thereof.

Description

Technical Field

[0001] The present application relates to the field of pesticide acaricides, and in particular to a preparation method of trifluoroethyl sulfoxide-substituted aromatic compounds and intermediates thereof. Background Art

[0002] As the problem of pesticide resistance of agricultural mites is becoming increasingly serious, it is necessary to continuously develop acaricides with novel structures, unique mechanisms of action, environmental friendliness, high efficiency and low toxicity. Trifluoroethyl sulfide (sulfoxide) substituted aromatic compounds are a new type of acaricide with excellent acaricidal activity.

[0003] Chinese patent application CN110028431A discloses a trifluoroethyl sulfoxide substituted aryl compound as shown in general formula a-2 and its synthesis route. The specific reaction formula is as follows: compound c (trifluoroethyl sulfide substituted aniline) is used as a starting material, reacted with compound d (ortho-halogenated methylbenzoyl halide) to obtain a compound of general formula b-1, then oxidized to obtain a sulfoxide compound b-2, and finally subjected to intramolecular cyclization to obtain a compound of general formula a-2; or the compound of general formula b-1 is first subjected to intramolecular cyclization to obtain a compound of general formula a-1, and finally subjected to sulfide oxidation to obtain a compound of general formula a-2.

[0004]

[0005] Chinese patent application CN115701423A discloses another synthetic route, as shown below: a compound of formula k (substituted aniline) is used as a starting reactant, and condensed with a phthalic anhydride compound j to obtain a compound of formula i, which is then subjected to a sulfonation reaction to obtain a sulfonyl chloride compound of formula h. The sulfonyl chloride compound undergoes a reduction reaction to obtain a sulfide compound g, which is then subjected to an alkylation reaction to obtain a trifluoroethyl sulfide compound f, and finally subjected to an oxidation reaction to obtain a trifluoroethyl sulfoxide-substituted aromatic compound shown in a compound of formula e.

[0006]

[0007] The above-mentioned synthesis method disclosed in the prior art has the problems of high raw material cost, complex route, low final product yield, involving dangerous processes such as zinc powder reduction, etc., large amount of three wastes, not environmentally friendly, and not conducive to large-scale production.

[0008] Therefore, researchers in this field have been committed to continuously developing lower-cost, more environmentally friendly, and more efficient synthetic routes to prepare trifluoroethyl sulfoxide-substituted aromatic compound acaricides for large-scale production. Summary of the invention

[0009] In order to solve the technical problems existing in the prior art, the present application provides a preparation method of trifluoroethyl sulfoxide substituted aryl compounds and intermediates thereof. The preparation method described in the present application uses low-priced substituted benzene as a starting material, undergoes sulfonation, reduction, alkylation, nitration oxidation, reduction, and intermolecular substitution splicing in six steps, and obtains trifluoroethyl sulfoxide substituted aryl compounds in high yield. The preparation method has short steps, simple operation, environmental friendliness, low cost, high yield, and is more suitable for large-scale industrial production.

[0010] In a first aspect, the present application provides a method for preparing a trifluoroethyl sulfoxide-substituted aryl compound represented by formula I, comprising the following steps:

[0011] Step 1): subjecting the substituted benzene compound represented by formula VII to a sulfonation reaction to obtain a sulfonyl chloride compound represented by formula VI;

[0012] Step 2): subjecting the compound represented by formula VI to a reduction reaction to obtain a disulfide compound represented by formula V;

[0013] Step 3): subjecting the compound represented by formula V to an alkylation reaction to obtain a trifluoroethyl sulfide compound represented by formula IV;

[0014] Step 4): subjecting the compound represented by formula IV to a nitration-oxidation reaction to obtain a meta-nitro-substituted trifluoroethylsulfoxide benzene compound represented by formula III;

[0015] Step 5): subjecting the compound represented by formula III to a reduction reaction to obtain a trifluoroethylsulfoxide benzene compound represented by formula II substituted with an m-amino group;

[0016] Step 6): reacting the compound represented by formula II with the o-halomethylbenzoyl halide compound represented by formula VIII to obtain the compound represented by formula I;

[0017]

[0018] R1 is selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy;

[0019] R2 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, R2 is located at the ortho position or meta position of R1;

[0020] R3-R6 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C6-C10 aryl, 5-10 membered heteroaryl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, or two adjacent groups in R3-R6 together with the carbon atom to which they are attached form a 3-8 membered ring group;

[0021] R7 and R8 are each independently selected from halogen.

[0022] The halogen described in the present application is selected from fluorine, chlorine, bromine and iodine.

[0023] In one group of embodiments, R1 is selected from halogen, cyano, preferably, R1 is selected from fluorine, chlorine or bromine.

[0024] In one group of embodiments, R2 is selected from C1-C6 alkyl, C1-C6 alkoxy, preferably methyl, ethyl, methoxy, ethoxy, more preferably R2 is selected from methyl, methoxy located at the meta position of R1, and ethyl located at the ortho position of R1.

[0025] In one group of embodiments, R1 is selected from fluorine and R2 is selected from methyl at the meta position, or R1 is selected from chlorine and R2 is selected from methoxy at the meta position, or R1 is selected from bromine and R2 is selected from ethyl at the ortho position.

[0026] In one group of embodiments, R2 is located at the meta or para position relative to the nitro or amino group in the compounds of formula II or III.

[0027] In one group of embodiments, R3-R6 are each independently selected from hydrogen, halogen such as bromine, nitro, or two adjacent groups in R3-R6 together with the carbon atom to which they are attached form a 5-6 membered aromatic ring group, such as a benzene ring.

[0028] In one group of embodiments, the trifluoroethyl sulfoxide-substituted aryl compound represented by Formula I is selected from the following compounds:

[0029]

[0030] In the preparation method described in the present application, in step 1), the sulfonating agent is selected from one or more of sulfuric acid, chlorosulfonic acid, and dichlorothionyl. The amount of the sulfonating agent used is 1 to 10 equivalents of the compound represented by formula VII, preferably 2 to 5 equivalents. In step 1), solvent A is used, and solvent A is selected from one or more of 1,2-dichloroethane, dichloromethane, chloroform, cyclohexane, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, and acetonitrile. The reaction temperature of step 1) is between -10°C and the boiling point of the solvent A.

[0031] Specifically, the compound represented by formula VII is reacted with a sulfonating agent in solvent A at a temperature ranging from -10°C to the boiling point of solvent A to obtain the compound represented by formula VI, such as reacting at a temperature of 0-20°C.

[0032] In the preparation method described in the present application, in step 2), a reducing agent A is used, and the reducing agent A is selected from one or more of sodium hypophosphite, sodium hydrosulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfide, and hydrazine hydrate. The amount of reducing agent A is 0.5 to 10 equivalents of the compound shown in formula VI, preferably 1 to 5 equivalents. In step 2), a solvent B is used, and the solvent B is selected from one or more of ethyl acetate, isopropyl acetate, methyl acetate, 1,2-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, toluene, xylene, trimethylbenzene, chlorobenzene, cyclohexane, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, acetone, methyl isobutyl ketone, water, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature of step 2) is 0°C to the boiling point of the solvent B.

[0033] Specifically, the compound represented by formula VI reacts with reducing agent A in solvent B at a temperature ranging from 0°C to the boiling point of the solvent to obtain the compound represented by formula V, such as reacting at a temperature of 20-80°C.

[0034] In the preparation method described in the present application, in step 3), the alkylation reaction is carried out in the presence of a trifluoroethylating agent, a reducing agent B and a base; the trifluoroethylating agent is selected from one or more of 2,2,2-trifluoroiodoethane, 2,2,2-trifluoroethylbenzenesulfonate, 2,2,2-trifluoroethyl p-toluenesulfonate, and 2,2,2-trifluoroethyl methanesulfonate; the reducing agent B is selected from one or more of bleaching powder, i.e., sodium formaldehyde sulfoxylate, hydrosulfite, sodium pyrosulfite, sodium sulfide, sodium thiosulfate, sodium hypophosphite, and hydrazine hydrate; the base is selected from an organic base or an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate, phosphate, hydrogen phosphate, alkoxide, organic amine, etc., specifically sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, trimethylamine, triethylamine, pyridine, DBU, and DIEA. The amount of the trifluoroethylating agent is 1.5 to 5 equivalents of the compound shown in formula V, preferably 2 to 3 equivalents. The amount of the reducing agent B is 0.5 to 10 equivalents of the compound shown in formula V, preferably 1 to 5 equivalents. The amount of the base is 0.5 to 10 equivalents of the compound shown in formula V, preferably 1 to 5 equivalents. Step (3) uses solvent C, which is selected from one or more of ethyl acetate, isopropyl acetate, methyl acetate, 1,2-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, toluene, xylene, trimethylbenzene, chlorobenzene, cyclohexane, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, acetone, methyl isobutyl ketone, water, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature of step 3) is 0°C to the boiling point of the solvent C.

[0035] Specifically, the compound represented by formula V is reacted with a trifluoroethylating agent, a base, and a reducing agent B in a solvent C at a temperature between 0°C and the boiling point of the solvent C to obtain a compound represented by formula IV, such as reacting at a temperature between 20-80°C.

[0036] In the preparation method described in the present application, in step 4), the compound shown in formula IV and nitric acid are simultaneously subjected to nitration and thioether oxidation reactions in sulfuric acid as a solvent to obtain a compound shown in formula III. Specifically, after nitric acid is added dropwise to sulfuric acid, the compound shown in formula IV is added dropwise to react. The concentration of the nitric acid is 60% or more, preferably 65% ​​or more, such as fuming nitric acid; its amount is 1 to 3 equivalents of the compound shown in formula IV, preferably 2 to 3 equivalents. The concentration of the sulfuric acid is 90% or more, preferably 95% or more, and more preferably concentrated sulfuric acid; its amount is 1 to 20 equivalents of the compound shown in formula IV, preferably 2 to 10 equivalents. The temperature when the compound shown in formula IV is added dropwise and during the reaction is -10 to 70°C, preferably 0 to 40°C, and more preferably 0 to 10°C.

[0037] In the preparation method described in the present application, in step 5), a transition metal reducing agent is used, preferably one or more selected from nickel, palladium, and tin, more preferably selected from Raney nickel and palladium carbon (such as 10% palladium carbon). The amount of the transition metal reducing agent is 0.001 to 1 equivalents of the compound shown in formula III, preferably 0.01 to 0.05 equivalents. In step 5), solvent D is used, selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, methyl acetate, 1,2-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, toluene, xylene, trimethylbenzene, chlorobenzene, cyclohexane, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, acetone, methyl isobutyl ketone, water, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature of step 5) is 0°C to the boiling point of the solvent D.

[0038] Specifically, the compound represented by formula III reacts with a transition metal reducing agent in a solvent D at a temperature ranging from 0°C to the boiling point of the solvent to obtain the compound represented by formula II, such as reacting at a temperature of 20-80°C.

[0039] In the preparation method described in the present application, in step 6), R7 and R8 are each independently selected from chlorine and bromine; preferably, the compound represented by formula VIII is an o-chloromethylbenzoyl chloride compound represented by formula VIII-1 or an o-bromomethylbenzoyl chloride compound represented by formula VIII-2; The amount of the compound shown in formula VIII is 1 to 3 equivalents of the compound shown in formula II, preferably 1 to 1.5 equivalents. Step 6) The reaction is carried out in the presence of a base, the base is selected from an organic base or an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate, phosphate, hydrogen phosphate, alkoxide, organic amine, etc., specifically sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, trimethylamine, triethylamine, pyridine, DBU, DIEA, one or more. The amount of the base used is 1 to 10 equivalents of the compound shown in formula II, preferably 2 to 5 equivalents. Step 6) uses a solvent E selected from one or more of ethyl acetate, isopropyl acetate, methyl acetate, 1,2-dichloroethane, dichloromethane, chloroform, acetonitrile, benzene, toluene, xylene, trimethylbenzene, chlorobenzene, cyclohexane, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, acetone, methyl isobutyl ketone, water, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. The reaction temperature of step 6) is between -10°C and the boiling point of the solvent E.

[0040] Specifically, the compound represented by formula II and the o-halomethylbenzoyl halide compound represented by formula VIII and a base are reacted in solvent E at a temperature ranging from -10°C to the boiling point of the solvent, such as at a temperature of 0-50°C.

[0041] In a second aspect, the present application also provides a meta-nitro-substituted trifluoroethylsulfoxide benzene compound as shown in formula III,

[0042]

[0043] R1 is selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy;

[0044] R2 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and R2 is located at the ortho position or meta position relative to R1.

[0045] In one group of embodiments, R1 is selected from halogen, preferably, R1 is selected from fluorine, chlorine or bromine.

[0046] In one group of embodiments, R2 is selected from C1-C6 alkyl, C1-C6 alkoxy, preferably methyl, methoxy, ethyl, ethoxy.

[0047] In one group of embodiments, R2 is located at the meta or para position to the nitro group.

[0048] In one group of embodiments, R1 is selected from fluorine, R2 is selected from methyl located at the meta position of R1; or R1 is selected from chlorine, R2 is selected from methoxy located at the meta position of R1; R1 is selected from bromine, R2 is selected from ethyl located at the ortho position of R1.

[0049] In one embodiment, the m-nitro-substituted trifluoroethylsulfoxide benzene compound represented by formula III is selected from the following compounds:

[0050]

[0051] In the third aspect, the present application also provides a method for preparing the meta-nitro-substituted trifluoroethylsulfoxide benzene compound represented by formula III described in the second aspect, which is prepared by steps 1) to 4) as described in the first aspect.

[0052] Those skilled in the art will appreciate that the definitions and preferences described in one aspect of the present application are equally applicable to other aspects. Those skilled in the art will appreciate that each group of embodiments of each aspect of the present application can be combined in various ways without departing from the subject matter and ideas of the present application, and these combinations are also included in the scope of the present application.

[0053] After research, it is found that compared with the prior art, this application has at least the following beneficial effects:

[0054] The preparation method described in the present application uses low-cost substituted benzene as the starting material, undergoes sulfonation, reduction, alkylation, and nitration oxidation to prepare a meta-nitro-substituted trifluoroethyl sulfoxide benzene compound, and then undergoes nitro reduction to amino group and intermolecular substitution splicing reaction to obtain a trifluoroethyl sulfoxide-substituted aryl compound in high yield. The preparation method has short steps, simple operation, environmental friendliness, low cost, high yield, and is more suitable for large-scale industrial production.

[0055] Lower cost: The prior art uses substituted aniline as a raw material, and requires five steps of reaction to obtain a final product of trifluoroethyl sulfide (sulfoxide) substituted aromatic compound. Moreover, substituted aniline is expensive and generally requires two steps of nitration and reduction to prepare. The present application uses a cheaper substituted benzene as a starting material, and obtains the final product through six steps of reaction, which is lower in cost, more efficient, and more suitable for large-scale production and expansion.

[0056] Fewer hazardous processes: The prior art involves the oxidation of trifluoroethyl sulfide to sulfoxide, which needs to be carried out separately, and the oxidation reaction is a hazardous process; the present application simultaneously completes the two hazardous processes of nitration and oxidation in a one-step reaction, which is more suitable for large-scale production.

[0057] High total yield: The present invention uses substituted benzene as the starting material and undergoes 6 steps of reaction to obtain the final product, the yield of each step of the reaction is more than 95%, and the total yield of the synthetic route is high.

[0058] Environmentally friendly: The reduction reaction of sulfonyl chloride involved in the prior art requires the use of a zinc powder / hydrochloric acid system, which produces a large amount of hydrogen, is relatively dangerous, and usually requires the use of a large excess of zinc powder. Post-processing will produce a large amount of three wastes, which is not only costly but also not conducive to environmental protection. The two-step reduction involved in this application: Step 2) using sodium hypophosphite or hydrosulfite to reduce sulfonyl chloride, the reaction aqueous phase only has sodium salt produced by the reducing agent; Step 5) using Raney nickel or palladium carbon to reduce the nitro group, only using a catalytic amount of reducing agent, the reaction produces less three wastes, lower cost, and more environmentally friendly. DETAILED DESCRIPTION

[0059] The present invention is further described below with reference to the examples; however, these examples do not limit the scope of the present invention. Unless otherwise stated, all reactants used in the examples are obtained from commercial sources; the instruments and equipment used in the synthesis experiments and product analysis and detection are conventional instruments and equipment commonly used in organic synthesis.

[0060] Embodiment 1:

[0061]

[0062] Add m-fluorotoluene (100 g, 1 equiv) and 500 g DCE to a 1 L reaction bottle, cool to 10°C, weigh chlorosulfonic acid (210 g, 2 equiv) and dropwise add to the reaction bottle, react at 10°C for 1 h. After the reaction is completed, add ice water to quench, separate the liquids, and concentrate the organic phase to obtain 180 g of 2-methyl-4-fluoro-benzenesulfonyl chloride with an HPLC purity of 97% and a yield of 95%.

[0063] 1 H NMR (300MHz, Chloroform-d) δ 8.09 (dd, J = 8.8, 5.4 Hz, 1H), 7.11 (ddt, J = 11.8, 8.4, 4.0 Hz, 2H), 2.79 (s, 3H).

[0064] Example 2-1:

[0065]

[0066] To a 1L reaction bottle, add 2-methyl-4-fluoro-benzenesulfonyl chloride (50 g, 1 equiv), isopropyl acetate 250 g, sodium hypophosphite monohydrate (38.2 g, 1.5 equiv), heat to 60 ° C and stir for 4 h, then cool to room temperature, add 300 g of water, separate the liquids, and concentrate the organic phase to obtain 33.9 g of (2-methyl-4-fluoro)phenyl disulfide with HPLC purity of 98%, quantitative content of 96%, and yield of 96%.

[0067] 1 H NMR (300MHz, Chloroform-d) δ7.36 (dd, J = 8.6, 5.8 Hz, 2H), 6.92 (ddd, J = 9.5, 2.8, 0.8 Hz, 2H), 6.88-6.75 (m, 2H), 2.38 (s, 6H). GC-MS(m / z):282.0.

[0068] Example 2-2:

[0069]

[0070] To a 1L reaction bottle, 2-methyl-4-fluoro-benzenesulfonyl chloride (50 g, 1 equiv), 250 g of dioxane, and hydrosulfite (62.7 g, 1.5 equiv) were added. The temperature was raised to 60°C and stirred for 4 h, then the dioxane was removed by concentration under reduced pressure. 300 g of water was added, and 300 g of ethyl acetate was used for extraction and separation. The organic phase was concentrated to obtain 34.5 g of (2-methyl-4-fluoro)phenyl disulfide with HPLC purity of 98%, quantitative content of 95%, and yield of 96%.

[0071] Example 3-1:

[0072]

[0073] To a 500 ml reaction bottle, (2-methyl-4-fluoro)phenyl disulfide (70 g, 1 equiv), 350 g of dioxane, sodium sulfide nonahydrate (48.6 g, 2.0 equiv), potassium carbonate (68.5 g, 2.0 equiv), and 2,2,2-trifluoroethyl p-toluenesulfonate (138.7 g, 2.2 equiv) were added, and the temperature was raised to 50° C. and stirred for 1 h. The reaction mixture was concentrated to remove dioxane, and water and ethyl acetate were added to extract the liquid. The organic phase was concentrated to obtain 118.1 g of (2,2,2-trifluoroethyl) (2-methyl-4-fluoro)phenyl sulfide with HPLC purity of 98%, quantitative content of 94%, and yield of 98%.

[0074] 1 H NMR (300MHz, Chloroform-d) δ7.51 (dd, J=8.6, 5.7Hz, 1H), 7.03-6.82 (m, 2H), 3.30 (q, J=9.7Hz, 2H), 2.49 (s, 3H). GC-MS(m / z):224.1.

[0075] Example 3-2:

[0076]

[0077] To a 500 ml reaction bottle, (2-methyl-4-fluoro)phenyl disulfide (50 g, 1 equiv), DMF 350 g, bleaching powder (41.8 g, 2.0 equiv), sodium carbonate (37.9 g, 2.0 equiv), and 2,2,2-trifluoroiodoethane (92.6 g, 2.5 equiv) were added, and the temperature was raised to 50 ° C. and stirred for 30 min. The reaction was concentrated to remove DMF, and water and ethyl acetate were added to extract the liquid. After the organic phase was concentrated, 83.1 g of (2,2,2-trifluoroethyl) (2-methyl-4-fluoro)phenyl sulfide was obtained, with HPLC purity of 98%, quantitative content of 93%, and yield of 97%.

[0078] Example 4-1:

[0079]

[0080] To a 100 ml reaction bottle, add concentrated sulfuric acid (49.5 g, 6 eq), add 65% nitric acid (24.0 g, 3 eq), cool to 0 ° C, continue to add (2,2,2-trifluoroethyl) (2-methyl-4-fluoro) phenyl sulfide (23.1 g, 1 eq), control the temperature at 0-5 ° C during the addition process, after the addition is complete, keep warm at 0-5 ° C for 1 h, add the reaction solution dropwise into ice water, filter, and dry the filter cake to obtain 30.3 g of white solid (2,2,2-trifluoroethyl)-((2-methyl-4-fluoro-5-nitro) phenyl) sulfoxide with HPLC purity of 95%, quantitative content of 92%, and yield of 95%.

[0081] 1 H NMR (300MHz, Chloroform-d) δ8.71 (d, J = 7.4 Hz, 1H), 7.27 (d, J = 4.1 Hz, 1H), 3.65–3.36 (m, 2H), 2.50 (s, 3H). LC-MS(m / z):286.0[M+1] + .

[0082] Example 4-2:

[0083]

[0084] To a 100 ml reaction bottle, add concentrated sulfuric acid (43.7 g, 5 eq), cool to 0 ° C, add fuming nitric acid (14.0 g, 2.5 eq) dropwise, and continue to add (2,2,2-trifluoroethyl) (2-methyl-4-fluoro) phenyl sulfide (20.0 g, 1 eq) dropwise. The temperature during the addition process is controlled at 0-5 ° C. After the addition is completed, keep warm at 0-5 ° C for 1 h. The reaction solution is added dropwise into ice water, filtered, and the filter cake is dried to obtain 25.9 g of white solid (2,2,2-trifluoroethyl)-((2-methyl-4-fluoro-5-nitro) phenyl) sulfoxide. The HPLC purity is 96%, the quantitative content is 94%, and the yield is 96%.

[0085] Example 5-1:

[0086]

[0087] To a 500 ml high-pressure reactor, (2,2,2-trifluoroethyl)-((2-methyl-4-fluoro-5-nitro)phenyl)sulfoxide (30 g, 1 equiv), 150 g of methanol, and Raney nickel (0.6 g, 2 w / w%) were added. After nitrogen was replaced in the reactor, hydrogen was replaced to 3 MPa, the temperature was raised to 60 ° C. and reacted for 5 h. The temperature was cooled to room temperature, filtered, and concentrated to obtain 27.1 g of (2-fluoro-4-methyl-5-(2,2,2-trifluoroethyl)sulfinyl)aniline. The HPLC purity was 99%, the quantitative content was 98%, and the yield was 99%.

[0088] 1 H NMR (300MHz, Methanol-d4) δ7.90 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 10.9 Hz, 1H), 4.00 (dq, J = 14.8, 10.4 Hz, 1H), 3.76 (dq, J = 14.8, 10.3 Hz, 1H), 2.43 (s, 3H). LC-MS(m / z):256.0[M+1] + .

[0089] Example 5-2:

[0090]

[0091] To a 500 ml high-pressure reactor, (2,2,2-trifluoroethyl)-((2-methyl-4-fluoro-5-nitro)phenyl)sulfoxide (30 g, 1 equiv), 150 g of methanol, and 10% wet palladium carbon (0.9 g, 3 w / w%) were added. After nitrogen was replaced in the reactor, hydrogen was replaced to 3 MPa, the temperature was raised to 60 ° C. and reacted for 5 h. The temperature was cooled to room temperature, filtered, and concentrated to obtain 27.8 g of (2-fluoro-4-methyl-5-(2,2,2-trifluoroethyl)sulfinyl)aniline. The HPLC purity was 98%, the quantitative content was 97%, and the yield was 99%.

[0092] Example 6-1:

[0093]

[0094] To a 500 ml reaction bottle, (2-fluoro-4-methyl-5-(2,2,2-trifluoroethyl)sulfinyl)aniline (20 g, 1 equiv) and DCE 80 g were added, stirred at room temperature, sodium bicarbonate (14.5 g, 2.2 equiv) was added in batches, stirred for 0.5 h, and 2-chloromethylbenzoyl chloride (16.2 g, 1.1 equiv) was added dropwise. After stirring at room temperature for 5 h, solid sodium hydroxide (3.1 g, 1 equiv) was added in batches. After stirring for 1 h, 40 g of water was added, the liquids were separated, and the organic phase was concentrated and slurried with 40 g of cyclohexane to obtain 28.2 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one with HPLC purity of 98%, quantitative content of 98%, and yield of 95%.

[0095] 1H NMR (300MHz, DMSO-d6) δ8.14(d,J=7.7Hz,1H),7.81(dt,J=7.6,1.1Hz,1H),7.77-7.65(m,2H),7.57(ddd,J=8.2,6.3,2.1Hz,1 H), 7.47 (d, J = 11.4Hz, 1H), 4.98 (d, J = 3.2Hz, 2H), 4.22 (dq, J = 14.6, 10.9Hz, 1H), 4.01 (dq, J = 14.7, 10.8Hz, 1H), 2.42 (s, 3H). LC-MS(m / z):372.1[M+1] + .

[0096] Example 6-2:

[0097]

[0098] To a 500 ml reaction bottle, (2-fluoro-4-methyl-5-(2,2,2-trifluoroethyl)sulfinyl)aniline (20 g, 1 equiv) and DCE 80 g were added and stirred at room temperature. Potassium carbonate (32.5 g, 3 equiv) was added in batches. After stirring for 0.5 h, 2-chloromethylbenzoyl chloride (17.6 g, 1.2 equiv) was added dropwise. After stirring at room temperature for 5 h, 40 g of water was added, the liquids were separated, and the organic phase was concentrated and slurried with 40 g of cyclohexane to obtain 29.1 g of 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one as a white solid with HPLC purity of 98%, quantitative content of 97%, and yield of 96%.

[0099] Example 6-3:

[0100]

[0101] To a 250 ml reaction bottle, (2-fluoro-4-methyl-5-(2,2,2-trifluoroethyl)sulfinyl)aniline (10 g, 1 equiv) and DCE 40 g were added and stirred at room temperature. Sodium bicarbonate (8.2 g, 2.5 equiv) was added in batches. The temperature was lowered to 0° C., and 4-bromo-2-chloromethylbenzoyl chloride (8.8 g, 1.2 equiv) was added dropwise after stirring for 0.5 h. After reacting for 1 h, solid sodium hydroxide (1.6 g, 1 equiv) was added in batches. The stirring was continued for 1 h. 20 g of water was added, and the liquids were separated. After the organic phase was concentrated, 20 g of cyclohexane was added to make pulp to obtain 29.1 g of white solid 5-bromo-2-(2-fluoro-4-methyl-5-((2,2,2-trifluoromethyl)sulfinyl)phenyl)isoindol-1-one with HPLC purity of 98%, quantitative content of 97%, and yield of 96%.

[0102] 1 H NMR(300MHz,Chloroform-d)δ7.96(d,J=8.8Hz,1H),7.57-7.52(m,2H),7.53(dt,J=2.2,1.0H z, 1H), 7.10 (dd, J = 7.9, 0.7Hz, 1H), 4.90 (d, J = 1.1Hz, 2H), 3.58 (q, J = 9.1Hz, 2H), 2.46 (s, 3H).

[0103] Example 6-4:

[0104]

[0105] To a 250 ml reaction bottle, (2-fluoro-4-methyl-5-(2,2,2-trifluoroethyl)sulfinyl)aniline (10 g, 1 equiv) and DCE 40 g were added and stirred at room temperature. Sodium bicarbonate (8.2 g, 2.5 equiv) was added in batches. The temperature was lowered to 15° C., and 5-nitro-2-chloromethylbenzoyl chloride (10.1 g, 1.1 equiv) was added dropwise after stirring for 0.5 h. After reacting for 1 h, solid sodium hydroxide (1.6 g, 1 equiv) was added in batches. The stirring was continued for 1 h. 20 g of water was added, the liquids were separated, and the organic phase was concentrated and slurried with 30 g of cyclohexane to obtain 16.5 g of white solid 6-nitro-2-(2-fluoro-4-methyl-5-((2,2,2-trifluoromethyl)sulfinyl)phenyl)isoindol-1-one with HPLC purity of 98%, quantitative content of 95%, and yield of 96%.

[0106] 1 H NMR(300MHz,Chloroform-d)δ8.73(d,J=2.2Hz,1H),8.18(dd,J=8.8,2.0Hz,1H),7.65(dt,J=8.8,1.0Hz,1H), 7.53(d,J=5.0Hz,1H), 7.10(dd,J=8.0,0.7Hz,1H), 4.96(d,J=1.0Hz,2H), 3.63(q,J=9.1Hz,2H), 2.47(s,3H). LC-MS(m / z):418.0[M+1] + .

[0107] Example 6-5:

[0108]

[0109] To a 250 ml reaction bottle, (2-fluoro-4-methyl-5-(2,2,2-trifluoroethyl)sulfinyl)aniline (5 g, 1 equiv) and DCE 40 g were added and stirred at room temperature. Sodium bicarbonate (4.4 g, 2.7 equiv) was added in batches. The temperature was lowered to 10° C. and stirred for 0.5 h. Then 3-(chloromethyl)-2-naphthoyl chloride (5.1 g, 1.1 equiv) was added dropwise. After reacting for 1 h, solid sodium hydroxide (0.8 g, 1 equiv) was added in batches. The stirring was continued for 1 h. 20 g of water was added and the liquids were separated. The organic phase was concentrated and slurried with 10 g of cyclohexane to obtain 8.1 g of white solid 2-(2-fluoro-4-methyl-5-(2,2,2-trifluoroethyl)sulfinyl)phenyl)-2,3-dihydro-1H-benzo[f]isoindol-1-one with HPLC purity of 98%, quantitative content of 97% and yield of 95%.

[0110] 1 H NMR(300MHz,Chloroform-d)δ8.44(d,J=1.9Hz,1H),7.93(d,J=2.0Hz,1H),7.90(dt,J=8.2,1.6Hz,1H),7.86-7.80(m,1H),7.5 7-7.48(m,2H),7.45(ddd,J=8.1,6.8,1.4Hz,1H),7.10(dd,J=8.0,0.7Hz,1H),4.91(s,2H),3.65(q,J=9.1Hz,2H),2.47(s,3H). LC-MS m / z):422.0[M+1] + .

[0111] Embodiment 7:

[0112]

[0113] Add m-chloroanisole (30 g, 1 equiv) and 200 g DCE to a 1 L reaction bottle, cool to 0°C, weigh chlorosulfonic acid (73.5 g, 3 equiv) and dropwise add to the reaction bottle, react at 0-10°C for 1 h. After the reaction is completed, add ice water to quench, separate the liquids, and concentrate the organic phase to obtain 49.9 g of 2-methoxy-4-chloro-benzenesulfonyl chloride, with an HPLC purity of 92% and a yield of 91%.

[0114] 1 H NMR (300MHz, Chloroform-d) δ7.85 (d, J = 9.6 Hz, 1H), 7.33 (dd, J = 9.6, 1.9 Hz, 1H), 7.13 (s, 1H), 3.77 (s, 3H).

[0115] Embodiment 8:

[0116]

[0117] To a 500 ml reaction bottle, add 2-methoxy-4-chloro-benzenesulfonyl chloride (40 g, 1 equiv), 200 g of dioxane, and sodium hydrosulfite (43.5 g, 1.5 equiv). Heat to 60 ° C. and stir for 4 h. Then, concentrate under reduced pressure to remove dioxane. Add 300 g of water and 300 g of ethyl acetate to extract the liquid. After concentrating the organic phase, 29.5 g of (2-methoxy-4-chloro)phenyl disulfide is obtained with HPLC purity of 97%, quantitative content of 93%, and yield of 95%.

[0118] 1 H NMR (300MHz, Chloroform-d) δ7.61 (d, J = 7.9 Hz, 2H), 7.19 (dd, J = 7.9, 2.0 Hz, 2H), 7.01 (d, J = 2.1 Hz, 2H), 3.88 (s, 6H).

[0119] Embodiment 9:

[0120]

[0121] To a 500 ml reaction bottle, (2-methoxy-4-chloro)phenyl disulfide (15 g, 1 equiv), DMF 105 g, bleaching powder (11.2 g, 2.0 equiv), potassium carbonate (13.2 g, 2.0 equiv), 2,2,2-trifluoroethyl p-toluenesulfonate (24.2 g, 2.0 equiv) were added, the temperature was raised to 50 ° C and stirred for 30 min, the reaction was concentrated to remove DMF, water and ethyl acetate were added to extract the liquid, and the organic phase was concentrated to obtain 26.3 g of (2,2,2-trifluoroethyl) (2-methoxy-4-chloro)phenyl sulfide with HPLC purity of 98%, quantitative content of 96%, and yield of 98%.

[0122] 1 H NMR (300MHz, Chloroform-d) δ7.32 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 8.1, 1.9 Hz, 1H), 7.01 (d, J = 1.9 Hz, 1H), 3.89 (s, 3H), 3.56 (q, J = 9.1 Hz, 2H). GC-MS(m / z):256.0.

[0123] Embodiment 10:

[0124]

[0125] To a 250 ml reaction bottle, add concentrated sulfuric acid (76.5 g, 10 eq), add 65% nitric acid (22.7 g, 3 eq), cool to 0 ° C, continue to add (2,2,2-trifluoroethyl) (2-methoxy-4-chloro) phenyl sulfide (20 g, 1 eq), control the temperature at 0-5 ° C during the addition process, after the addition is complete, keep warm at 0-5 ° C for 1 h, add the reaction solution dropwise into ice water, filter, and dry the filter cake to obtain 24.5 g of white solid (2,2,2-trifluoroethyl)-((2-methoxy-4-chloro-5-nitro) phenyl) sulfoxide with HPLC purity of 93%, quantitative content of 92%, and yield of 91%.

[0126] 1 H NMR (300MHz, Chloroform-d) δ 8.46 (s, 1H), 7.29 (s, 1H), 3.74 (d, J = 9.3Hz, 5H).

[0127]

[0128] To a 500 ml high-pressure reactor, (2,2,2-trifluoroethyl)-((2-methoxy-4-chloro-5-nitro)phenyl)sulfoxide (20 g, 1 equiv), 100 g of methanol, and 10% wet palladium carbon (0.6 g, 3 w / w%) were added. After nitrogen was replaced in the reactor, hydrogen was replaced to 3 MPa, the temperature was raised to 70 ° C. and reacted for 5 h. The temperature was cooled to room temperature, filtered, and concentrated to obtain 17.7 g of (2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)sulfinyl)aniline. The HPLC purity was 98%, the quantitative content was 97%, and the yield was 95%.

[0129] 1 H NMR (500MHz, Chloroform-d) δ7.05 (s, 1H), 6.79 (s, 1H), 4.78 (s, 2H), 3.77 (s, 3H), 3.69 (q, J = 9.0Hz, 2H).

[0130] Embodiment 12:

[0131]

[0132] To a 100 ml reaction bottle, (2-chloro-4-methoxy-5-(2,2,2-trifluoroethyl)sulfinyl)aniline (10 g, 1 equiv) and DCE 50 g were added, stirred at room temperature, sodium bicarbonate (6.5 g, 2.2 equiv) was added in batches, stirred for 0.5 h, and 2-chloromethylbenzoyl chloride (7.2 g, 1.1 equiv) was added dropwise. After stirring at room temperature for 5 h, solid sodium hydroxide (1.4 g, 1 equiv) was added in batches. After stirring for 1 h, 20 g of water was added, the liquids were separated, and the organic phase was concentrated and slurried with 20 g of cyclohexane to obtain 13.5 g of white solid 2-(2-chloro-4-methoxy-5-((2,2,2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one with HPLC purity of 97%, quantitative content of 97%, and yield of 93%.

[0133] 1 H NMR(300MHz,Chloroform-d)δ8.06(dd,J=8.0,1.6Hz,1H),7.57(s,1H),7.50–7.3 7(m,3H),7.12(s,1H),4.98(d,J=0.9Hz,2H),3.76(s,3H),3.66(q,J=9.0Hz,2H). LC-MS(m / z):404.0[M+1] + .

[0134] Embodiment 13:

[0135]

[0136] Add o-bromoethylbenzene (20 g, 1 equiv) and 100 g DCE to a 1 L reaction bottle, cool to 0°C, weigh chlorosulfonic acid (50.4 g, 4 equiv) and dropwise add to the reaction bottle, react at 0-10°C for 1 h. After the reaction is completed, add ice water to quench, separate the liquids, concentrate the organic phase to remove dichloroethane, add 50 g methyl tert-butyl ether to pulp, filter, and dry the filter cake to obtain 23.1 g of 3-ethyl-4-bromo-benzenesulfonyl chloride, HPLC purity 94%, yield 71%.

[0137] 1 H NMR (300MHz, Chloroform-d) δ7.81-7.74 (m, 2H), 7.64 (d, J = 9.6Hz, 1H), 2.65 (qd, J = 7.3, 0.9Hz, 2H), 1.25 (t, J = 7.3Hz, 3H).

[0138] Embodiment 14:

[0139]

[0140] To a 500 mL reaction bottle, 3-ethyl-4-bromo-benzenesulfonyl chloride (20 g, 1 equiv), isopropyl acetate 250 g, and hydrosulfite (18.5 g, 1.5 equiv) were added. The temperature was raised to 60 ° C. and stirred for 4 h. The reaction system was cooled to room temperature, 200 g of water was added and stirred, and the liquids were separated. After the organic phase was concentrated, 14.9 g of (3-ethyl-4-bromo)phenyl disulfide was obtained. The HPLC purity was 93%, the quantitative content was 91%, and the yield was 91%.

[0141] 1 H NMR (300MHz, Chloroform-d) δ7.45 (d, J=7.6Hz, 2H), 7.37-7.31 (m, 4H), 2.67 (qd, J=7.4, 0.9Hz, 4H), 1.24 (t, J=7.3Hz, 6H). GC-MS(m / z):432.9.

[0142] Embodiment 15:

[0143]

[0144] To a 500 ml reaction bottle, add (3-ethyl-4-bromo)phenyl disulfide (10 g, 1 equiv), DMF 70 g, bleaching powder (8.2 g, 3.0 equiv), potassium carbonate (9.6 g, 2.0 equiv), trifluoroiodoethane (13.1 g, 2.7 equiv), and heat to 50 ° C. and stir for 30 min. The reaction mixture is concentrated to remove DMF, and water and ethyl acetate are added to extract the liquid. After the organic phase is concentrated, 14.0 g of (2,2,2-trifluoroethyl) (3-ethyl-4-bromo)phenyl sulfide is obtained, with HPLC purity of 98%, quantitative content of 96%, and yield of 97%.

[0145] 1 H NMR(300MHz,Chloroform-d)δ7.38(s,1H),7.14(dd,J=8.1,2.3Hz,1H),7.06(dt,J=2.1 ,1.0Hz,1H),3.51(q,J=9.0Hz,2H),2.67(qd,J=7.3,1.0Hz,2H),1.24(t,J=7.3Hz,3H).

[0146] Embodiment 16:

[0147]

[0148] In a 100 ml reaction bottle, add concentrated sulfuric acid (29.7 g, 10 eq), add 65% nitric acid (9.8 g, 3 eq), cool to 0 ° C, continue to add (2,2,2-trifluoroethyl) (3-ethyl-4-bromo) phenyl sulfide (10 g, 1 eq), control the temperature at 0-5 ° C during the addition process, keep warm at 0-5 ° C for 1 hour after the addition is completed, add the reaction solution dropwise into ice water, and filter. Collect the filter cake and beat with 30 g of 1,2-dichloroethane, collect the filter cake after filtration, and dry it to obtain 7.9 g of white solid (2,2,2-trifluoroethyl)-((3-nitro-4-bromo-5-ethyl) phenyl) sulfoxide, HPLC purity 97%, quantitative content 95%, yield 65%.

[0149] 1 H NMR (300MHz, Chloroform-d) δ 8.27 (d, J = 2.2 Hz, 1H), 7.70 (dt, J = 1.9, 0.9 Hz, 1H), 3.65 (q, J = 9.0 Hz, 2H), 2.76 (qd, J = 7.3, 1.0 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H).

[0150] Embodiment 17:

[0151]

[0152] To a 250 ml high pressure reactor was added (2,2,2-trifluoroethyl)-((3-nitro-4-bromo-5-ethyl)phenyl)sulfoxide (7.0 g, 1 equiv), 50 g of methanol, and 10% wet palladium carbon (0.14 g, 2 w / w%). After nitrogen was replaced in the reactor, hydrogen was replaced to 3 MPa, the temperature was raised to 60 ° C for reaction for 5 h, the temperature was lowered to room temperature, filtered, and concentrated to obtain 6.3 g of (2-bromo-3-ethyl-5-(2,2,2-trifluoroethyl)sulfinyl)aniline with HPLC purity of 99%, quantitative content of 97%, and yield of 98%.

[0153] 1 H NMR(300MHz,Chloroform-d)δ7.16(dt,J=2.1,1.0Hz,1H),7.05(d,J=2.2Hz,1H),4.17(d,J=7.0Hz ,1H),4.11(d,J=7.0Hz,1H),3.61(q,J=9.0Hz,2H),2.66(qd,J=7.2,0.9Hz,2H),1.24–1.18(m,3H).

[0154] Embodiment 18:

[0155]

[0156] To a 100 ml reaction bottle, (2-bromo-3-ethyl-5-(2,2,2-trifluoroethyl)sulfinyl)aniline (5 g, 1 equiv) and DCE 30 g were added, stirred at room temperature, sodium carbonate (2.4 g, 1.5 equiv) was added in batches, stirred for 0.5 h, and 2-chloromethylbenzoyl chloride (3.7 g, 1.3 equiv) was added dropwise. After stirring at room temperature for 5 h, solid sodium hydroxide (0.6 g, 1 equiv) was added in batches. After stirring for 1 h, 10 g of water was added, the liquids were separated, and the organic phase was concentrated and slurried with 20 g of cyclohexane to obtain 6.5 g of white solid 2-(2-bromo-3-ethyl-5-((2,2,2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one with HPLC purity of 97%, quantitative content of 95%, and yield of 91%.

[0157] 1 H NMR(300MHz,Chloroform-d)δ8.07(dd,J=8.0,1.6Hz,1H),7.53–7.34(m,5H),4.94(d,J =1.0Hz, 2H), 3.57 (q, J = 9.0Hz, 2H), 2.67 (qd, J = 7.3, 1.1Hz, 2H), 1.21 (t, J = 7.3Hz, 3H). LC-MS(m / z):447.9[M+1] + .

[0158] Embodiment 19:

[0159]

[0160] Add m-cyanotoluene (20 g, 1 equiv) and 200 g DCE to a 1 L reaction bottle, cool to 5°C, weigh chlorosulfonic acid (80.1 g, 4 equiv) and dropwise add to the reaction bottle, and react at 5°C for 1 h. After the reaction is completed, add ice water to quench, separate the liquids, concentrate the organic phase to remove dichloroethane, add 80 g cyclohexane to slurry, filter and dry the filter cake to obtain 32.1 g of 2-methyl-4-cyano-benzenesulfonyl chloride, with HPLC purity of 93% and a yield of 81%.

[0161] 1 H NMR (300MHz, Chloroform-d) δ7.91 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.7, 2.1 Hz, 1H), 7.60-7.56 (m, 1H), 2.68 (s, 3H).

[0162] Embodiment 20:

[0163]

[0164] To a 1L reaction bottle, 2-methyl-4-chloro-benzenesulfonyl chloride (50 g, 1 equiv), 250 g isopropyl acetate, and sodium hypophosphite monohydrate (35.6 g, 1.5 equiv) were added. The temperature was raised to 60°C and stirred for 4 h. Then, 200 g of water was added. The liquids were separated and the organic phase was concentrated to obtain 34.8 g of (2-methyl-4-chloro)phenyl disulfide with HPLC purity of 98%, quantitative content of 95%, and yield of 94%.

[0165] 1 H NMR (300MHz, Chloroform-d) δ7.42(d,J=7.6Hz,2H),,7.27(dd,J=7.6,2.1Hz,2H),7.21(s,2H),2.42(s,6H). GC-MS (m / z): 315.0.

[0166] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0167] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0168] In addition, various embodiments of the present invention may be arbitrarily combined, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A method for preparing a trifluoroethyl sulfoxide-substituted aryl compound of formula I, characterized in that: The steps include: Step 1): subjecting the substituted benzene compound represented by formula VII to a sulfonation reaction to obtain a sulfonyl chloride compound represented by formula VI; Step 2): subjecting the compound represented by formula VI to a reduction reaction to obtain a disulfide compound represented by formula V; Step 3): subjecting the compound represented by formula V to an alkylation reaction to obtain a trifluoroethyl sulfide compound represented by formula IV; Step 4): subjecting the compound represented by formula IV to a nitration-oxidation reaction to obtain a meta-nitro-substituted trifluoroethylsulfoxide benzene compound represented by formula III; Step 5): subjecting the compound represented by formula III to a reduction reaction to obtain a trifluoroethylsulfoxide benzene compound represented by formula II substituted with an m-amino group; Step 6): reacting the compound represented by formula II with the o-halomethylbenzoyl halide compound represented by formula VIII to obtain the compound represented by formula I; R1 is selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy; R2 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, R2 is located at the ortho position or meta position of R1; R3-R6 are each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, C6-C10 aryl, 5-10 membered heteroaryl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, or two adjacent groups in R3-R6 together with the carbon atom to which they are attached form a 3-8 membered ring group; R7 and R8 are each independently selected from halogen.

2. The preparation method according to claim 1, characterized in that: R1 is selected from fluorine, chlorine or bromine.

3. The preparation method according to claim 1 or 2, characterized in that: R2 is selected from methyl, ethyl, methoxy, ethoxy, preferably, R2 is selected from methyl and methoxy located at the meta position of R1, and ethyl located at the ortho position of R1.

4. The preparation method according to any one of claims 1 to 3, characterized in that: R2 is located at the meta-position or para-position of the nitro or amino group in the compounds of formula II and formula III.

5. The preparation method according to any one of claims 1 to 4, characterized in that: R3-R6 are each independently selected from hydrogen, halogen, nitro, or two adjacent groups in R3-R6 together with the carbon atom to which they are connected form a 5-6 membered aromatic ring group.

6. The preparation method according to claim 5, characterized in that: R3-R6 are each independently selected from hydrogen, bromine, nitro, or two adjacent groups in R3-R6 together with the carbon atom to which they are connected form a benzene ring.

7. The preparation method according to claim 1, characterized in that: The trifluoroethyl sulfoxide substituted aryl compound shown in formula I is selected from the following compounds:

8. The preparation method according to any one of claims 1 to 7, characterized in that: In step 1), the sulfonating agent is selected from one or more of sulfuric acid, chlorosulfonic acid, and thionyl chloride; preferably, the amount of the sulfonating agent is 1 to 10 equivalents of the compound represented by formula VII, more preferably 2 to 5 equivalents.

9. The preparation method according to any one of claims 1 to 8, characterized in that: In step 2), a reducing agent A is used, and the reducing agent A is selected from one or more of sodium hypophosphite, hydrosulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfide, and hydrazine hydrate; preferably, the amount of reducing agent A is 0.5 to 10 equivalents of the compound represented by formula VI, and more preferably 1 to 5 equivalents.

10. The preparation method according to any one of claims 1 to 9, characterized in that: In step 3), the alkylation reaction is carried out in the presence of a trifluoroethylating agent, a reducing agent B and a base.

11. The preparation method according to claim 10, characterized in that: The trifluoroethylating agent is selected from one or more of 2,2,2-trifluoroiodoethane, 2,2,2-trifluoroethylbenzenesulfonate, 2,2,2-trifluoroethyl p-toluenesulfonate, and 2,2,2-trifluoroethyl methanesulfonate; the reducing agent B is selected from one or more of bleaching powder, hydrosulfite, sodium pyrosulfite, sodium sulfide, sodium thiosulfate, sodium hypophosphite, and hydrazine hydrate; preferably, the amount of the trifluoroethylating agent is 1.5 to 5 equivalents of the compound shown in formula V, and the amount of the reducing agent B is 0.5 to 10 equivalents of the compound shown in formula V; more preferably, the amount of the trifluoroethylating agent is 2 to 3 equivalents of the compound shown in formula V, and the amount of the reducing agent B is 1 to 5 equivalents of the compound shown in formula V.

12. The preparation method according to any one of claims 1 to 11, characterized in that: In step 4), the compound represented by formula IV is simultaneously subjected to nitration and thioether oxidation reaction with nitric acid in sulfuric acid as a solvent to obtain a compound represented by formula III; preferably, after nitric acid is added dropwise to sulfuric acid, the compound represented by formula IV is then added dropwise to react.

13. The preparation method according to claim 12, characterized in that: The concentration of the nitric acid is above 60%, and its usage is 1 to 3 equivalents of the compound shown in formula IV. The concentration of the sulfuric acid is above 90%, and its usage is 1 to 20 equivalents of the compound shown in formula IV. Preferably, the concentration of the nitric acid is above 65%, and its usage is 2 to 3 equivalents of the compound shown in formula IV. The sulfuric acid is concentrated sulfuric acid, and its usage is 2 to 10 equivalents of the compound shown in formula IV.

14. The method according to any one of claims 1 to 13, characterized in that: In step 5), a transition metal reducing agent is used, preferably one or more selected from nickel, palladium, and tin, more preferably selected from Raney nickel and palladium on carbon.

15. The preparation method according to claim 14, characterized in that: The amount of the transition metal reducing agent used is 0.001 to 1 equivalent, preferably 0.01 to 0.05 equivalent, of the compound represented by formula III.

16. The preparation method according to any one of claims 1 to 15, characterized in that: R7 and R8 are each independently selected from chlorine and bromine; preferably, the compound represented by formula VIII is an o-chloromethylbenzoyl chloride compound represented by formula VIII-1 or an o-bromomethylbenzoyl chloride compound represented by formula VIII-2; 17. The preparation method according to any one of claims 1 to 16, characterized in that: In step 6), the amount of the compound represented by formula VIII is 1 to 3 equivalents of the compound represented by formula II, and more preferably 1 to 1.5 equivalents.

18. The preparation method according to any one of claims 1 to 17, characterized in that: The step 6) is reacted in the presence of a base.

19. A meta-nitro-substituted trifluoroethylsulfoxide benzene compound of formula III, R1 is selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy; R2 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and R2 is located at the ortho position or meta position relative to R1.

20. The compound according to claim 19, characterized in that R1 is selected from fluorine, chlorine or bromine.

21. The compound according to claim 19 or 20, characterized in that R2 is selected from C1-C6 alkyl, C1-C6 alkoxy, preferably methyl, methoxy, ethyl, ethoxy.

22. The compound according to any one of claims 19 to 21, characterized in that R2 is located at the meta-position or para-position of the nitro group.

23. The compound according to claim 19, characterized in that The m-nitro-substituted trifluoroethylsulfoxide benzene compound shown in formula III is selected from the following compounds:

24. A method for preparing a meta-nitro-substituted trifluoroethylsulfoxide benzene compound represented by formula III according to any one of claims 19 to 23, characterized in that: It is prepared according to steps 1)-4) of any one of claims 1 and 8-18.

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