Preparation method of sulfoxide compound, aniline compound and preparation method of aniline compound

Abstract

The invention relates to the field of chemical synthesis of pesticides, and discloses a preparation method of a sulfoxide compound, an aniline compound and a preparation method of the aniline compound. The method comprises the following steps: (1) carrying out diazotization reaction and coupling reaction on a compound III to prepare a compound II; (2) carrying out alkylation reaction and oxidation reaction on the compound II in the step (1) to prepare a compound I; wherein R3 is selected from H, a cyano group, an acyl group of C3-C6 or a thioester group of C2-C4. According to the method, the final product compound I is synthesized through the intermediate compound III, so that the method has the beneficial effects of less three wastes generated in the reaction process, higher synthetic route yield and low comprehensive cost. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of pesticide chemical synthesis, and in particular to a preparation method of a sulfoxide compound and an aniline compound and a preparation method thereof. Background Art

[0002] Trifluoroethyl sulfide (sulfoxide) substituted benzene compounds are a new type of highly effective miticide. Patents CN110028431, CN 111978225, CN111978226, and CN 112166105 disclose trifluoroethyl sulfide (sulfoxide) substituted benzene compounds, which can be used to control various harmful mites. The above patents also disclose the synthesis route and method of the compounds, and the specific reaction formula is shown in route a. In route a, aniline substituted with trifluoroethyl sulfide and a halogenated methylene benzoyl halide compound are subjected to substitution reaction, ring-closing reaction, and oxidation reaction to obtain the target product, or the target product is obtained by substitution reaction, oxidation reaction, and ring-closing reaction (see route a for details);

[0003]

[0004]

[0005] The synthesis of the initial raw material trifluoroethyl sulfide substituted aniline in route a is synthesized by the following method. Patents US2012053052 and CN102341376 disclose that substituted aniline is used as the starting raw material for synthesis, and is prepared by acylation, sulfonation, reduction, hydrolysis, and alkylation, as follows (route a-1):

[0006]

[0007] In addition, patent CN115701423 discloses that phthalic anhydride and substituted aniline are used as starting materials and then condensed, sulfonylated, reduced, alkylated, and oxidized to obtain the final target product;

[0008]

[0009] Among the above methods, the preparation methods of routes a and b are difficult to obtain raw materials (aniline substituted with trifluoroethyl sulfide and 2-fluoro-4-methylaniline, both of which have high use costs), the synthetic process routes are complex, and the total yield is low, which is not conducive to large-scale production. At the same time, the sulfidation of the substituted aniline is obtained by chlorosulfonic acid chlorination and then reduction, and a large amount of wastewater and irritating waste gas are generated in the post-reaction treatment process, which not only affects production safety and cost, but also affects environmental safety. In addition, the initial raw materials in the synthesis are all 2-fluoro-4-methylaniline. Referring to CN109704987A and literature (Journal of Organic Chemistry, 1961, vol. 26, p. 3351-3356; Journal of Organic Chemistry, 1998, vol. 63, # 23, p. 8448-8454; J. Org. Chem. 2012, 77, 7471-7478), it can be known that the synthesis cost of the compound is relatively high, and the risk factor of its production process is not low. It involves dangerous processes such as nitration, high temperature and high pressure, and azofluorination, which makes it difficult to industrialize. In order to obtain the target product in a simpler, safer and more environmentally friendly way, it is necessary to actively study a more reasonable preparation method. Summary of the invention

[0010] The purpose of the present invention is to overcome the problems of low yield, large amount of waste water and waste gas polluting the environment and high process risk in the prior art, and to provide a preparation method of sulfoxide compounds and aniline compounds and preparation methods thereof.

[0011] In order to achieve the above object, the first aspect of the present invention provides a method for preparing a sulfoxide compound, the method comprising:

[0012] (1) subjecting compound III to diazotization reaction and coupling reaction to obtain compound II;

[0013]

[0014] (2) subjecting the compound II in step (1) to an alkylation reaction and an oxidation reaction to obtain a compound I;

[0015]

[0016] Wherein, R3 is selected from H, cyano, C3-C6 acyl or C2-C4 thioester.

[0017] The second aspect of the present invention provides an aniline compound, characterized in that the compound has a structure shown in Formula III:

[0018] The third aspect of the present invention provides a method for preparing an aniline compound, characterized in that the method comprises:

[0019] Compound IV is contacted with a cyclization reagent to undergo a cyclization reaction to obtain the obtained compound;

[0020] Wherein, the compound IV and the cyclization reagent have the same definitions as those described in the first aspect of the present invention.

[0021] Through the above technical scheme, the preparation method of the sulfoxide compound of the present invention has the effects of mild reaction conditions, easy availability of reaction raw materials, simple reaction operation and easy industrialization; at the same time, since the technical scheme of the present invention synthesizes the final product compound I through the intermediate compound III, it does not involve chlorosulfonic acid compounds, and adopts the diazotization coupling method to carry out benzene ring sulfidation, so that the three wastes generated in the reaction process are much less than the former; and the synthetic route of the present invention has a high yield and low comprehensive cost. DETAILED DESCRIPTION

[0022] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0023] As mentioned above, the first aspect of the present invention provides a method for preparing a sulfoxide compound, the method comprising:

[0024] (1) subjecting compound III to diazotization reaction and coupling reaction to obtain compound II;

[0025]

[0026] (2) subjecting the compound II in step (1) to an alkylation reaction and an oxidation reaction to obtain a compound I;

[0027]

[0028] Wherein, R3 is selected from H, cyano, C3-C6 acyl or C2-C4 thioester.

[0029] In some embodiments of the present invention, preferably, in step (1), the compound III is first subjected to a diazotization reaction with an inorganic acid A and a diazotizing agent in the presence of a solvent A, and then subjected to a coupling reaction with a sulfur-containing coupling reagent in the presence of a catalyst A and a solvent A to obtain the compound II.

[0030] In some embodiments of the present invention, preferably, the solvent A is selected from C1-C10 The organic solvent is further preferably at least one of acetonitrile, tetrahydrofuran, acetone, methyl isopropyl ketone, ethyl acetate, methyl acetate, dichloromethane, dichloroethane, dioxane, cyclohexane, n-hexane and toluene, and more preferably toluene.

[0031] In some embodiments of the present invention, preferably, the inorganic acid A is selected from at least one of hydrochloric acid, phosphoric acid and sulfuric acid, more preferably hydrochloric acid.

[0032] In some embodiments of the present invention, the diazotizing agent is selected from nitrite and / or nitrite ester compounds, preferably at least one of sodium nitrite, potassium nitrite, ethyl nitrite, methyl nitrite, isopropyl nitrite and butyl nitrite, more preferably sodium nitrite;

[0033] In some embodiments of the present invention, preferably, the catalyst A is selected from at least one of iron, copper, ferrous chloride, ferrocene, zinc, nickel chloride and nickel, preferably copper.

[0034] In some embodiments of the present invention, preferably, the sulfur-containing coupling reagent is selected from at least one of thiocyanate, hydrogen sulfide, sulfide and C1-C6 organic acid salt, and is further preferably selected from at least one of sodium thiocyanate, ammonium thiocyanate, potassium thiocyanate, mercuric thiocyanate, cuprous thiocyanate, copper thiocyanate, silver thiocyanate, cobalt thiocyanate, ferric thiocyanate, sodium hydrogen sulfide, potassium hydrogen sulfide, sodium sulfide, potassium sulfide, potassium ethyl xanthate, potassium thiopropionate, sodium thiopropionate, sodium thiopivalate, potassium thiopivalate, sodium 2,2-dimethylthiobutyrate, potassium 2,2-dimethylthiobutyrate and potassium 3,3-dimethylthiobutyrate, and is more preferably sodium thiocyanate.

[0035] In some embodiments of the present invention, preferably, in step (2), the compound II undergoes an alkylation reaction with an alkylating agent in the presence of a base A and a solvent B, and then is contacted with a catalyst A1 and / or an oxidant in the presence of a solvent C to undergo an oxidation reaction to obtain compound I.

[0036] In some embodiments of the present invention, preferably, the base A is selected from at least one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, triethylamine, tri-n-butylamine, pyridine, morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 3,4-dimethylaminopyridine, more preferably potassium carbonate.

[0037] In some embodiments of the present invention, preferably, the solvent B is selected from C1-C 10The organic solvent is further preferably at least one of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dioxane, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, dimethyl carbonate, cyclohexane, acetone, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, and more preferably N,N-dimethylformamide.

[0038] In some embodiments of the present invention, preferably, the alkylating agent is selected from trifluoroethyl sulfonate, halogenated trifluoroiodoethane, further preferably 2,2,2-trifluoroethyl methyl sulfonate, 2,2,2-trifluoroethyl benzene sulfonate, 2,2,2-trifluoroethyl-4-toluene sulfonate, 2,2,2-trifluoroethyl trifluoromethyl sulfonate, 1,1,1-trifluoroiodoethane, 1,1,1-trifluorochloroethane, 1,1,1-trifluorobromoethane, more preferably at least one of 2,2,2-trifluoroethyl-4-toluene sulfonate and 1,1,1-trifluoroiodoethane.

[0039] In some embodiments of the present invention, preferably, the alkylation reaction is carried out in a nitrogen atmosphere.

[0040] In some embodiments of the present invention, preferably, the solvent C is selected from C1-C 10 The organic solvent is further preferably at least one of dichloromethane, ethylene dichloride, chloroform, tetrahydrofuran, dioxane, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, cyclohexane, acetone, toluene, xylene, N,N-dimethylacetamide and N-methylpyrrolidone, more preferably ethylene dichloride and / or toluene.

[0041] In some embodiments of the present invention, preferably, the catalyst A1 is at least one of TEMPO and its derivatives or TEMPO derivatives, nitrosyl oxidation catalysts Nor-AZADO and 1-Me-AZADO, more preferably TEMPO and / or 4-OH-TEMPO.

[0042] In some embodiments of the present invention, preferably, the oxidant is selected from at least one of air, oxygen, manganese oxides or manganates with a valence state of 4-7, iron halides, iron nitrates, sodium tungstate, potassium or sodium salts of hypohalous acids, potassium or sodium salts of halogenous acids, potassium or sodium salts of halogen acids, potassium or sodium salts of perhalic acids, iodobenzene diacetate, performic acid, peracetic acid, peroxydichloroacetic acid, peroxydifluoroacetic acid, peroxytrifluoroacetic acid, potassium or sodium persulfate, ammonium persulfate, sodium or potassium nitrite and benzene compounds containing nitro groups, more preferably air and / or nitrates.

[0043] In some embodiments of the present invention, preferably, the inorganic acid A is selected from an aqueous solution of an acid, and its concentration is 10-30 wt %, preferably 15-25 wt %.

[0044] In some embodiments of the present invention, preferably, the molar ratio of the inorganic acid A, the diazotizing agent, the catalyst A and the sulfur-containing coupling agent to the compound III is 2-6: 1.001-1.2: 0.005-0.2: 1.001-1.5: 1, preferably 2.5-4: 1.01-1.1: 0.01-0.1: 1.05-1.2: 1. This molar ratio range can maximize the yield of both the decarboxylation reaction and the coupling reaction.

[0045] In some embodiments of the present invention, preferably, the mass ratio of the solvent A to the compound III is 0.5-5:1, preferably 2.5-3.5:1.

[0046] In some embodiments of the present invention, preferably, the temperature of the diazotization reaction is -10 to 8°C, more preferably -2 to 5°C.

[0047] In some embodiments of the present invention, preferably, the temperature of the coupling reaction is -10 to 10°C, more preferably -5 to 5°C.

[0048] In some embodiments of the present invention, preferably, the product of the diazotization reaction is added to the reaction system of the coupling reaction in a dropwise manner, and the dropwise addition time is 0.5-3 h, preferably 1-1.5 h.

[0049] In some embodiments of the present invention, preferably, the reaction time of the diazotization reaction is 0.5-5 h, more preferably 1.5-4 h; the reaction time of the coupling reaction is 0.5-6 h, more preferably 1-3.5 h.

[0050] In some embodiments of the present invention, preferably, the molar ratio of the base A, the alkylating agent and the compound II is 1.01-3: 1.001-1.5: 1, preferably 1.1-2.5: 1.01-1.3: 1. This molar ratio range can maximize the yield of the alkylation reaction.

[0051] In some embodiments of the present invention, preferably, the mass ratio of the solvent B to the compound II is 0.5-5:1, preferably 2-4:1.

[0052] In some embodiments of the present invention, preferably, the temperature of the alkylation reaction is 0-120°C, more preferably 20-80°C.

[0053] In some embodiments of the present invention, preferably, the mass ratio of the solvent C to the compound II is 1-6:1, more preferably 2-4.5:1.

[0054] In some embodiments of the present invention, preferably, the temperature of the oxidation reaction is -10°C to 80°C, more preferably 0-65°C.

[0055] In some embodiments of the present invention, preferably, the mass ratio of the catalyst A1 to the compound II is 0.0005-0.2, more preferably 0.001-0.05.

[0056] In some embodiments of the present invention, preferably, the molar ratio of the oxidant to compound II is 0.005-1.5:1, more preferably 0.01-1.1:1; preferably, when the oxidant is selected from air or an air combination, the air flow rate is 5-1000 mL / min, more preferably 80-500 mL / min.

[0057] In some embodiments of the present invention, preferably, the reaction time of the alkylation reaction is 0.5-10 h, more preferably 2-7 h.

[0058] In some embodiments of the present invention, preferably, the reaction time of the oxidation reaction is 0.5-10 h, more preferably 1.5-6 h.

[0059] In some embodiments of the present invention, preferably, the compound III is prepared by a condensation reaction of compound IV and a cyclization agent in the presence of a solvent D, followed by an intramolecular cyclization reaction under the action of a base B, or a condensation reaction of compound IV and a cyclization agent in the presence of a solvent D; and finally a reduction reaction in a catalyst B and / or a reducing agent and a solvent F;

[0060]

[0061] In some embodiments of the present invention, preferably, the cyclization reagent is selected from phthalic anhydride or 2-chloromethylbenzoyl chloride.

[0062] In some embodiments of the present invention, preferably, the base B is selected from sodium carbonate, potassium carbonate, sodium (or potassium) salt of C1-C4 alcohol (including solution), sodium hydroxide, potassium hydroxide, sodium hydride, triethylamine, tri-n-butylamine, pyridine, morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, sodium hydride, more preferably sodium carbonate and sodium methoxide.

[0063] Preferably, the solvent D is selected from C1-C 10 The organic solvent is further preferably at least one of dichloromethane, dichloroethane, chloroform, cyclohexane, n-hexane, tetrahydrofuran, dioxane, toluene, benzene, chlorobenzene, dichlorobenzene and xylene, and more preferably dichloroethane and / or toluene.

[0064] In some embodiments of the present invention, preferably, the catalyst B is selected from Raney nickel, carbon containing 1-10 wt% palladium, carbon containing 1-10 wt% platinum, zinc powder, iron powder or copper powder, preferably Raney nickel.

[0065] In some embodiments of the present invention, preferably, the reducing agent is at least one of hydrogen, sodium cyanoborohydride, borane dimethyl sulfide, sodium borohydride, diborane, lithium aluminum hydride, zinc powder, iron powder, and aluminum powder, more preferably hydrogen and sodium borohydride.

[0066] In some embodiments of the present invention, preferably, the solvent F is selected from at least one of methanol, ethanol, propanol, n-butanol, isopropanol, tetrahydrofuran, ethylene dichloride, dichloromethane, dimethyl ketone, cyclohexanol, ethylene glycol, carbon tetrachloride, dioxane, acetic acid, oxalic acid, malonic acid, benzene toluene, xylene, halogenated benzene, trifluorotoluene; more preferably, ethylene dichloride and / or methanol, tetrahydrofuran. In some embodiments of the present invention, preferably, the mass ratio of the solvent D to the compound IV is 1-6:1, preferably 2.5-4:1.

[0067] In some embodiments of the present invention, preferably, in the condensation reaction, when the cyclization reagent is phthalic anhydride and / or 2-chloromethylbenzoyl chloride, the molar ratio to compound IV is 1.001-1.2:1, more preferably 1.005-1.1:1.

[0068] In some embodiments of the present invention, preferably, the temperature of the condensation reaction is 60-150°C, more preferably 80-115°C.

[0069] In some embodiments of the present invention, preferably, the molar ratio of the base B to the compound IV is 0.5-1.5: 1, more preferably 0.6-1.1: 1. This molar ratio range can maximize the yield of the ring-closing reaction.

[0070] In some embodiments of the present invention, preferably, the reaction time of the condensation reaction is 0.5 to 8 hours, more preferably 2 to 6 hours.

[0071] In some embodiments of the present invention, preferably, the temperature of the ring-closing reaction is -10°C to 80°C, more preferably 0-60°C.

[0072] In some embodiments of the present invention, preferably, the reaction time of the ring-closing reaction is 0.5-8 h, more preferably 1-6 h.

[0073] In some embodiments of the present invention, preferably, the mass ratio of the catalyst B to the compound IV is 0.005-0.1: 1, more preferably 0.01-0.05: 1. This molar ratio range can maximize the yield of the reduction reaction.

[0074] In some embodiments of the present invention, preferably, the mass ratio of the solvent F to the compound IV is 1-8:1, more preferably 2.5-6:1.

[0075] In some embodiments of the present invention, preferably, the pressure of the hydrogen is 0.5-4.5 MPa, more preferably 1-2.5 MPa, or the molar ratio of the reducing agent to compound IV is 1.001-15: 1, more preferably 2.01-12: 1. This pressure range can maximize the yield of the reduction reaction.

[0076] In some embodiments of the present invention, preferably, the temperature of the reduction reaction is 0-100°C, more preferably 20-80°C, and preferably, the reaction time of the reduction reaction is 1-15h, more preferably 3-10h.

[0077] In some embodiments of the present invention, preferably, the compound IV is prepared by subjecting the compound V to an acylation reaction, an amination reaction, or by subjecting the compound V to a hydrolysis reaction in a base C solution and then subjecting the compound V to a degradation reaction in the presence of a solvent J, a halogenating agent, and a base D;

[0078]

[0079] In some embodiments of the present invention, preferably, R1 is selected from -CN, -CX3, and -COOR.

[0080] In some embodiments of the present invention, preferably, R is selected from one of H or C1-C6 alkyl; and X is selected from halogen.

[0081] In some embodiments of the present invention, preferably, the process of the acylation reaction is that when R1 is selected from -CX3, compound V undergoes an acylation reaction with an organic acid under the action of a Lewis acid to obtain an acylated product, or when R1 is selected from -COOR and R is H, compound V undergoes an acylation reaction with an acylating agent in the presence of a solvent G and a catalyst C.

[0082] In some embodiments of the present invention, preferably, the process of the amination reaction is that the product of the acylation reaction is subjected to an amination reaction with an amination reagent in the presence of a solvent G.

[0083] In some embodiments of the present invention, preferably, the Lewis acid is selected from at least one of tin dichloride, tin tetrachloride, ferric chloride, ferrous chloride, zinc dichloride, aluminum chloride, copper chloride, copper bromide, copper iodide and boron trifluoride, more preferably ferric chloride and / or aluminum chloride.

[0084] In some embodiments of the present invention, preferably, the organic acid is selected from at least one of formic acid, acetic acid, oxalic acid, propionic acid and malonic acid, more preferably oxalic acid.

[0085] In some embodiments of the present invention, preferably, the catalyst C is N,N-dimethylformamide.

[0086] In some embodiments of the present invention, preferably, the acylating agent is selected from at least one of thionyl chloride, oxalyl chloride, phosgene and phosphorus trichloride, more preferably thionyl chloride.

[0087] In some embodiments of the present invention, preferably, the solvent G is selected from C1-C 10 The organic solvent is further preferably at least one of dichloroethane, toluene, dichloromethane, xylene, cyclohexane and n-hexane, and more preferably dichloroethane.

[0088] In some embodiments of the present invention, preferably, the aminating agent is selected from ammonia gas or ammonia water, more preferably ammonia water.

[0089] In some embodiments of the present invention, preferably, the alkali C in the alkali C solution is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate, more preferably sodium carbonate.

[0090] In some embodiments of the present invention, preferably, the solvent J is selected from at least one of water, ethanol, methanol, isopropanol, cyclohexane, ethylene dichloride, tetrahydrofuran, dioxane, toluene, benzene, xylene, halogenated benzene, methyl acetate, ethyl acetate, methyl isopropyl ketone, dimethyl ketone and di-tert-butyl ketone, more preferably water.

[0091] In some embodiments of the present invention, preferably, the halogenating agent is selected from at least one of chlorine, bromine, iodine, halogenated succinimide, trichloroisocyanuric acid, tribromoisocyanuric acid, sodium hypochlorite, sodium hypobromite and sodium hypoiodite, more preferably at least one of bromine, chlorine, sodium hypochlorite and sodium hypobromite.

[0092] In some embodiments of the present invention, preferably, the base D is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide, more preferably sodium hydroxide.

[0093] In some embodiments of the present invention, preferably, the molar ratio of the acylating agent to the compound V is 1.001-1.5: 1, more preferably 1.01-1.1: 1. This mass ratio range can maximize the yield of the acylation reaction.

[0094] In some embodiments of the present invention, preferably, the molar ratio of the Lewis acid to the compound V is 0.005-1.2:1, more preferably 0.01-1.1:1.

[0095] In some embodiments of the present invention, preferably, the molar ratio of the organic acid to the compound V is 0.51-1.2:1; more preferably 0.55-1.05.

[0096] In some embodiments of the present invention, preferably, the mass ratio of the solvent G to the compound V is 0.5-5:1, more preferably 2-3.5:1.

[0097] In some embodiments of the present invention, preferably, the mass ratio of the catalyst C to the compound V is 0.001-0.01:1, more preferably 0.01-0.03:1.

[0098] In some embodiments of the present invention, preferably, the mass ratio of the solvent J to the compound V is 2-8:1, more preferably 3-5:1.

[0099] In some embodiments of the present invention, preferably, the molar ratio of the aminating agent to the compound V is 1.01-4.0:1, more preferably 1.5-2.5:1.

[0100] In some embodiments of the present invention, preferably, the temperature of the acylation reaction is 20-180°C, more preferably 80-150°C.

[0101] In some embodiments of the present invention, preferably, the temperature of the amination reaction is -10 to 10°C, more preferably -5 to 5°C.

[0102] In some embodiments of the present invention, preferably, the concentration of the base C solution is 5-50%, more preferably 10-30%.

[0103] In some embodiments of the present invention, preferably, the mass ratio of the base C solution to the compound V is 0.5-6:1, more preferably 1-3:1. This mass ratio range can maximize the yield of the hydrolysis reaction.

[0104] In some embodiments of the present invention, preferably, the temperature of the hydrolysis reaction is 0-80°C, more preferably 55-60°C.

[0105] In some embodiments of the present invention, preferably, the ratio of the solvent J to the compound V is 0.5-8:1, more preferably 3-6:1.

[0106] In some embodiments of the present invention, preferably, the molar ratio of the halogenating agent to the compound V is 1.01-3.5:1, preferably 1.05-2.5:1.

[0107] In some embodiments of the present invention, preferably, the concentration of the base D solution is 10-50%, more preferably 15-30%; and the molar ratio of the base D to the compound V is 1.1-4.0:1, preferably 1.5-2.6:1.

[0108] In some embodiments of the present invention, preferably, the temperature of the degradation reaction is -10 to 100°C, more preferably -5 to 80°C.

[0109] In some embodiments of the present invention, preferably, the amination reaction time is 0.5-5h, more preferably 1.5-3h;

[0110] In some embodiments of the present invention, preferably, the degradation reaction time is 1-10 hours, more preferably 3-7 hours.

[0111] In some embodiments of the present invention, preferably, the compound V is prepared by subjecting the compound VI to a substitution reaction with a substitution reagent in the presence of a base E and a solvent K, and then to a deesterification hydrolysis reaction with an inorganic acid B in the presence of a solvent L, and finally to a decarboxylation reaction in the presence of a catalyst D and a solvent Q;

[0112]

[0113] In some embodiments of the present invention, preferably, R1 is selected from -CN, -CX3, -COOR; and R2 is selected from halogen.

[0114] In some embodiments of the present invention, preferably, is selected from one of H or C1-C6 alkyl; and X is selected from halogen.

[0115] In some embodiments of the present invention, preferably, the base E is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and sodium / potassium salts of C1-C4 alcohols, more preferably potassium carbonate.

[0116] In some embodiments of the present invention, preferably, the solvent K is selected from C1-C 10 The organic solvent is further preferably at least one selected from tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and sulfolane, and more preferably N,N-dimethylformamide.

[0117] In some embodiments of the present invention, preferably, the substitution reagent is selected from at least one of dimethyl malonate, diethyl malonate, dipropyl malonate, dibutyl malonate, diisopropyl malonate, diisobutyl malonate, di-tert-butyl malonate, methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, butyl cyanoacetate, isopropyl cyanoacetate, tert-butyl cyanoacetate, isobutyl cyanoacetate and isopentyl cyanoacetate, more preferably methyl cyanoacetate and dimethyl malonate.

[0118] In some embodiments of the present invention, preferably, the solvent L is selected from at least one of formic acid, acetic acid, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene and water, more preferably acetic acid.

[0119] In some embodiments of the present invention, preferably, the inorganic acid B is selected from at least one of hydrochloric acid, sulfuric acid and phosphoric acid, more preferably sulfuric acid.

[0120] In some embodiments of the present invention, preferably, the catalyst D is selected from one of silver halide, silver carbonate, silver acetate, silver nitrate, nickel chloride, nickel acetate, manganese acetate, palladium acetate, palladium chloride, palladium carbonate, copper chloride and iron chloride, preferably silver acetate and / or silver carbonate.

[0121] In some embodiments of the present invention, preferably, the solvent Q is selected from at least one of tetrahydrofuran, acetonitrile, dioxane, ethylene dichloride, ethyl acetate, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and sulfolane, more preferably dioxane and / or tetrahydrofuran.

[0122] In some embodiments of the present invention, preferably, the molar ratio of the base E, the substitution reagent and the compound VI is 1.01-1.5: 1.001-1.5: 1, preferably 1.05-1.2: 1.05-1.2: 1. This molar ratio range can maximize the yield of the substitution reaction.

[0123] In some embodiments of the present invention, preferably, the mass ratio of the solvent K to the compound VI is 0.5-5:1, preferably 1-3.0:1.

[0124] In some embodiments of the present invention, preferably, the temperature of the substitution reaction is 0-100°C, preferably 20-60°C.

[0125] In some embodiments of the present invention, preferably, the molar ratio of the inorganic acid B to the compound VI is 1-4:1, more preferably 1.5-3:1. This molar ratio range can maximize the yield of the deesterification hydrolysis reaction.

[0126] In some embodiments of the present invention, preferably, the inorganic acid B is selected from an aqueous solution of an acid, and its concentration is 20-90 wt %, preferably 36-80 wt %.

[0127] In some embodiments of the present invention, preferably, the mass ratio of the solvent L to the compound VI is 0.5-5:1, preferably 1-3.5:1.

[0128] In some embodiments of the present invention, preferably, the temperature of the deesterification hydrolysis reaction is 50-110°C, preferably 90-95°C.

[0129] In some embodiments of the present invention, preferably, the deesterification hydrolysis reaction time is 1-15 h, preferably 6-11 h.

[0130] In some embodiments of the present invention, preferably, the molar ratio of the catalyst D to the compound VI is 0.001-0.05: 1, more preferably 0.003-0.015: 1. This molar ratio range can maximize the yield of the decarboxylation reaction.

[0131] In some embodiments of the present invention, preferably, the mass ratio of the solvent Q to the compound VI is 0.5-4:1, preferably 1-2.5:1.

[0132] In some embodiments of the present invention, preferably, the temperature of the decarboxylation reaction is 20-150°C, preferably 40-60°C.

[0133] In some embodiments of the present invention, preferably, the substitution reaction time is 0.5-12 h, more preferably 1.5-8 h.

[0134] In some embodiments of the present invention, preferably, the reaction time of the decarboxylation reaction is 0.5-10 h, preferably 1.5-8 h.

[0135] In some embodiments of the present invention, preferably, after the reaction is completed, post-treatment is carried out; wherein the post-treatment includes at least one of cooling, filtering, rinsing, drying, reducing pressure, distillation, adjusting pH value, extraction, concentration, quenching, standing and recycling.

[0136] The second aspect of the present invention provides an aniline compound, characterized in that the compound has a structure shown in Formula III: Compound III.

[0137] The third aspect of the present invention provides a method for preparing an aniline compound, characterized in that the method comprises:

[0138] Compound IV is contacted with a cyclization reagent to undergo a cyclization reaction to obtain the obtained compound;

[0139] Wherein, the compound IV and the cyclization reagent have the same definitions as those described in the first aspect of the present invention.

[0140] The present invention will be described in detail below by way of examples. In the following examples, the amounts of reactants and products were measured by liquid chromatography (Agilent HPLC 1260); 1 H NMR data were measured by nuclear magnetic resonance; the conversion and selectivity of the reaction were calculated by the following formula:

[0141] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%;

[0142] Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%;

[0143] Yield = actual mass of target product / theoretical mass of target product × 100%.

[0144] In the following examples, the raw material 2,4-difluoro-5-nitrotrichloromethylbenzene is purchased 2,4-difluoro-5-nitrotrifluoromethylbenzene synthesized by conventional methods, and the remaining raw materials are commercially available products of Shanghai Aladdin Biochemical Technology Co., Ltd. and Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0145] The present invention will be described in detail below through examples.

[0146] Example 1

[0147] 2-Fluoro-4-methyl-5-nitrobenzoic acid (Compound V-1):

[0148] In a four-necked reaction bottle equipped with a mechanical stirrer, a thermometer, a condenser, and a dropping funnel, compound VI-1 (2,4-difluoro-5-nitrobenzoic acid, 1 mol, 207.2 g), potassium carbonate (1.15 mol, 160.5 g), and DMF (518.1 g) were added in sequence, and methyl cyanoacetate (1.1 mol, 110.1 g) was added dropwise to the system, and the reaction temperature was controlled between 30-35°C for 5 hours. The temperature was lowered to 0-5°C and filtered, and the filtrate was distilled under reduced pressure to recover DMF. The residue was cooled to room temperature, and the pH was adjusted to neutral with hydrochloric acid. The layers were extracted with dichloroethane, and the organic phase was concentrated to obtain the substitution product (283.7 g, 93.5%), which was directly used in the next step;

[0149] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, the substituted product obtained in the previous step (283.7 g, 93.5%), acetic acid (518 g), and 80% sulfuric acid (2.1 mol, 257.3 g) were added in sequence, and the temperature was raised to 90-95°C, and the reaction was kept warm for 10 hours. After the reaction was completed, the acetic acid was recovered by vacuum distillation, the residue was extracted with dichloroethane, and the organic phase was concentrated to obtain a deesterification hydrolysis product (227.3 g, 94%), which was directly used in the next step;

[0150] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, the deesterified hydrolysis product obtained in the previous step (227.3 g, 94%), silver acetate (0.005 mol, 0.85 g) and dioxane (414.5 g) were added in sequence, and the temperature was raised to 55-60°C and kept for 4 hours. After the reaction was completed, the solvent was recovered under reduced pressure, the residue was extracted with dichloroethane and water, and the organic phase was concentrated to obtain compound VI (180.4 g, 95%), with a yield of 86%;

[0151] Preparation of 2-fluoro-4-methyl-5-nitroaniline (Compound IV):

[0152] Compound V-1 (1.0 mol, 205.3 g), dichloroethane (615.9 g), and N,N-dimethylformamide (2.1 g) were added to a four-mouth reaction bottle equipped with a mechanical stirrer, a thermometer, and a condenser. The temperature was raised to 85°C, and thionyl chloride (1.05 mol, 126.2 g) was added dropwise to keep the temperature for 3 h. 25% ammonia water (2.2 mol, 308.4 g) was added to another four-mouth reaction bottle, and the temperature was lowered to 0°C. The above reaction liquid was added dropwise to the ammonia water, and the temperature was maintained at 0-5°C. The reaction was maintained for 1.5 h, and the mixture was returned to room temperature and stirred for 1 h. The filter cake was the amination reaction product (215.8 g, 90%), which was directly used in the next step.

[0153] Add the amination product (215.8 g, 90%) and water (718.5 g) obtained in the previous step to a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, cool to 0°C, and slowly introduce chlorine (1.08 mol, 77.4 g) into the system, then maintain the temperature at 3-7°C and react for 3.0 h. Slowly add the prepared 30% sodium hydroxide solution (2.2 mol, 293.3 g) dropwise to the reaction system, control the temperature at 5-10°C, dropwise for about 1 h, slowly raise the temperature to 60-65°C after the addition is completed, and react for 2 h. Extract with dichloroethane and separate the layers, and concentrate the organic phase to obtain compound IV (166.7 g, 96%) with a yield of 94.1%.

[0154] Preparation of 2-(5-amino-2-fluoro-4-methylphenyl)isoindolin-1-one (Compound III)

[0155] Compound IV (1.0 mol, 175.4 g) and dichloroethane (526.2 g) were added to a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser. 2-(chloromethyl)benzoyl chloride (1.05 mol, 208.9 g) was added dropwise under stirring. The temperature was raised to 80-85°C and the reaction was kept warm for 5 hours. The temperature was lowered to 0-5°C, and a 30% sodium methoxide solution (1.05 mol, 189.1 g) was slowly added dropwise to the system. The addition was completed in about 1.5 hours, and then the system temperature was raised to 20-25°C and the reaction was kept warm for 5 hours. After the reaction was completed, an appropriate amount of acetic acid was used to quench the sodium methoxide to obtain the mother liquor of the cyclization reaction product (1017.8 g, 27%), which was directly used in the next step;

[0156] The mother liquor (1017.8 g, 27%) of the product of the cyclization reaction in the previous step and Raney nickel (5.3 g) were added to a stainless steel reactor equipped with stirring, temperature display, and pressure gauge. The reaction cover was tightened, and the internal space of the reactor was replaced with nitrogen three times, and the internal space of the reactor was replaced with hydrogen three times. Then, 2.0 MPa of hydrogen was filled into the reactor, and the air inlet valve was closed. The reactor rpm = 700, and the temperature was controlled at 60-65 ° C for 8 hours (the hydrogen pressure was not less than 1.3 MPa during the reaction process, and the pressure was supplemented when insufficient). After the reaction was completed, the temperature was lowered and the pressure was released, the reaction liquid was filtered, the catalyst was recovered and applied, and the filtrate was concentrated to obtain compound III (251 g, 96%) with a yield of 94%.

[0157] The characterization analysis of compound III is as follows: 1 H NMR(400MHz,Chloroform-d)δ8.01(dd,J=7.4,2.0Hz,1H),7.58(td,J=7.5,2.0Hz,1H),7.56-7.49(m,1H),7.45( td,J=7.4,2.1Hz,1H),6.77-6.70(m,1H),6.40(d,J=5.7Hz,1H),4.89(d,J=1.0Hz,2H),4.56(s,2H),2.12(s,3H).

[0158] Preparation of 2-(2-fluoro-4-methyl-5-thiocyanatophenyl)isoindolin-1-one (II-1):

[0159] Into a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, compound III (264.2 g, 1 mol) and toluene (528.4 g) were added in sequence, and 20% hydrochloric acid (3.0 mol, 547.5 g) was slowly added dropwise under stirring, and stirred for 1 h. The temperature was lowered to -5-0°C, and 25% sodium nitrite solution (1.05 mol, 289.8 g) was added dropwise to the system under temperature control. The addition lasted for 1 h, and the mixture was kept at 0-5°C and stirred for 1 h. Sodium thiocyanate (1.08 mol, 98.3 g), 264.2 g toluene, and copper powder (0.05 mol, 3.2 g) were added in sequence to another reaction flask. The temperature was lowered to -5-0°C, and the above diazonium salt solution was added dropwise to the toluene system. The temperature of the addition process did not exceed 5°C, and the addition lasted for 1-1.5 h. The reaction was kept warm for 2 h. After the reaction was completed, the mixture was allowed to stand and the organic phase was concentrated to obtain compound II-1 (301.6 g, 91%) with a yield of 92%.

[0160] Preparation of 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one (Compound I):

[0161] Compound II-1 (2-(2-fluoro-4-methyl-5-thiocyanatophenyl)isoindolin-1-one, 1 mol, 307.6 g), potassium carbonate (1.9 mol, 265.3 g), DMF 922.7 g and 2,2,2-trifluoroethyl p-toluenesulfonate (1.1 mol, 285.4 g) were added to a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser. The temperature was raised to 70-75°C under nitrogen protection and the reaction was kept warm for 6 hours. The temperature was lowered to 0°C, filtered, and the filtrate was adjusted to a neutral pH with dichloroethane and water and hydrochloric acid. The filtrate was extracted and separated, and the organic phase was concentrated to obtain the alkylation product (366.7 g, 94%), which was directly used in the next step;

[0162] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, 922.7 g of dichloroethane, 4-hydroxy-2,2,6,6-tetramethylpiperidinyl nitroxide free radical (6.2 g), and ferric nitrate (15.4 g) were first added in sequence, and then the alkylation product (366.7 g, 94%) obtained in the previous step was added under stirring, and finally the air flow meter was turned on, the flow rate was adjusted to 200-240 mL / min, the temperature was raised to 55-60°C, and the reaction was kept warm for 5 hours. The temperature was lowered to room temperature, water was added for extraction and stratification, the organic phase was adjusted to a neutral pH with hydrochloric acid, the stratification was carried out, and the organic phase was concentrated to obtain compound I (368 g, 93%), with a yield of 92.2%.

[0163] The characterization analysis of compound I is as follows: 1H NMR(400MHz,Chloroform-d)δ8.01(dd,J=7.4,2.0Hz,1H),7.58(td,J=7.5,2.0Hz,1H),7.52(ddt,J=7.6,2.2,1.2Hz,1H),7.45( td,J=7.4,2.1Hz,1H),7.28(d,J=5.8Hz,1H),7.10(dd,J=8.8,1.2Hz,1H),4.89(d,J=0.9Hz,2H),3.35-3.25(m,2H),2.37(s,3H).

[0164] In summary, the total yield of compound I synthesized from compound VI-1 is 64.5%.

[0165] Example 2

[0166] 2-Fluoro-4-methyl-5-nitrobenzonitrile (Compound V-2):

[0167] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, a condenser, and a dropping funnel, compound VI-2 (2,4-difluoro-5-nitrobenzonitrile, 1 mol, 187.9 g), potassium carbonate (1.15 mol, 160.5 g), and DMF (469.6 g) were added in sequence, and methyl cyanoacetate (1.1 mol, 110.1 g) was added dropwise to the system. The reaction temperature was controlled between 30-35°C for 5 h, and the mixture was cooled to 0-5°C and filtered. The filtrate was distilled under reduced pressure to recover DMF, and the residue was cooled to room temperature. The pH was adjusted to neutral with hydrochloric acid, and the layers were extracted with dichloroethane. The organic phase was concentrated to obtain the substitution product (264.9 g, 92.4%), which was directly used in the next step;

[0168] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, the substituted product obtained in the previous step (264.9 g, 92.4%), acetic acid (469.6 g), and 80% sulfuric acid (2.1 mol, 257.3 g) were added in sequence, and the temperature was raised to 90-95°C, and the reaction was kept warm for 10 hours. After the reaction was completed, the acetic acid was recovered by vacuum distillation, the residue was extracted with dichloroethane, and the organic phase was concentrated to obtain a deesterification hydrolysis product (215.7 g, 86%), which was directly used in the next step;

[0169] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, the deesterification hydrolysis product obtained in the previous step (215.7 g, 86%), silver acetate (0.005 mol, 0.85 g) and dioxane (375.7 g) were added in sequence, and the temperature was raised to 55-60°C and kept for 4 hours. After the reaction was completed, the solvent was recovered under reduced pressure, and the residue was extracted with dichloroethane and water, and the organic phase was concentrated to obtain compound V-2 (152.3 g, 93%) with a yield of 78.6%;

[0170] Preparation of 2-fluoro-4-methyl-5-nitroaniline (Compound IV):

[0171] Compound V-2 (1.0 mol, 185.7 g) and 15% sodium carbonate solution (492.1 g) were added to a four-necked reaction bottle equipped with a mechanical stirrer, a thermometer, and a condenser. The mixture was heated to 55-60°C under stirring and kept for 5 hours. The mixture was cooled to 0-5°C and filtered. The filter cake was rinsed with cold water and dried to obtain a hydrolysis product (216.4 g, 87%), which was used directly in the next step.

[0172] Add the hydrolysis product (216.4 g, 87%) and water (718.5 g) obtained in the previous step to a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, cool to 0°C, and slowly introduce chlorine (1.08 mol, 77.4 g) into the system, then maintain the temperature at 3-7°C and react for 3.0 h. Slowly add the prepared 30% sodium hydroxide solution (2.2 mol, 293.3 g) dropwise to the reaction system, control the temperature at 5-10°C, dropwise for about 1 h, slowly heat to 60-65°C after the addition is complete, and react for 2 h. Extract with dichloroethane to separate the layers, and concentrate the organic phase to obtain compound IV (163.3 g, 95%) with a yield of 91.2%.

[0173] The yield of compound IV synthesized from compound VI-2 was 71.7%. The synthesis process from compound IV to compound I was carried out according to the method of Example 1. Combined with the yield of compound I synthesized from compound IV in Example 1, the total yield of compound I synthesized from compound VI-2 was calculated to be 57.2%;

[0174] Example 3: Compound V was synthesized from Compound VI-3;

[0175] Preparation of 2-fluoro-4-methyl-5-nitro-trichloromethylbenzene (Compound V-3):

[0176] In a four-necked reaction bottle equipped with a mechanical stirrer, a thermometer, a condenser, and a dropping funnel, compound VI-3 (2,4-difluoro-5-nitrotrichloromethylbenzene, 1 mol, 282.1 g), potassium carbonate (1.15 mol, 160.5 g), and DMF (705.2 g) were added in sequence, and methyl cyanoacetate (1.1 mol, 110.1 g) was added dropwise to the system, and the reaction temperature was controlled between 30-35°C for 5 hours. The temperature was lowered to 0-5°C and filtered, and the filtrate was distilled under reduced pressure to recover DMF. The residue was cooled to room temperature, and the pH was adjusted to neutral with hydrochloric acid. The layers were extracted with dichloroethane, and the organic phase was concentrated to obtain the substitution product (354 g, 92.4%), which was directly used in the next step;

[0177] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, the substituted product obtained in the previous step (354 g, 92.4%), acetic acid (705.2 g), and 80% sulfuric acid (2.1 mol, 257.3 g) were added in sequence, and the temperature was raised to 90-95°C, and the reaction was kept warm for 10 hours. After the reaction was completed, the acetic acid was recovered by vacuum distillation, the residue was extracted with dichloroethane, and the organic phase was concentrated to obtain a deesterification hydrolysis product (297.6 g, 91%), which was directly used in the next step;

[0178] In a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, the deesterification hydrolysis product obtained in the previous step (297.6 g, 91%), silver acetate (0.005 mol, 0.85 g) and dioxane (414.5 g) were added in sequence, and the temperature was raised to 55-60°C and kept for 4 hours. After the reaction was completed, the solvent was recovered under reduced pressure, and the residue was extracted with dichloroethane and water, and the organic phase was concentrated to obtain compound V-3 (238.1 g, 94%) with a yield of 82.1%;

[0179] Preparation of 2-fluoro-4-methyl-5-nitroaniline (Compound IV):

[0180] Compound V-3 (1.0 mol, 280.9 g), ferric chloride (2.8 g), and oxalic acid (54.6 g, 0.6 mol) were added to a four-mouth reaction bottle equipped with a mechanical stirrer, a thermometer, and a condenser. The temperature was slowly raised to 145-150°C and the reaction was kept warm for 2 hours. 25% ammonia water (2.2 mol, 308.4 g) was added to another four-mouth reaction bottle, and the temperature was lowered to 0°C. The reaction liquid of the above acylation reaction was added dropwise to the ammonia water. The temperature was maintained at 0-5°C. The reaction was maintained for 1.5 hours, and the mixture was returned to room temperature and stirred for 1 hour. The filter cake was the amination reaction product (216.2 g, 88%), which was directly used in the next step.

[0181] Add the amination product (216.2 g, 88%) and water (983.2 g) obtained in the previous step to a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, cool to 0°C, and slowly introduce chlorine (1.08 mol, 77.4 g) into the system, then maintain the temperature at 3-7°C and react for 3.0 h. Slowly add the prepared 30% sodium hydroxide solution (2.2 mol, 293.3 g) dropwise to the reaction system, control the temperature at 5-10°C, dropwise for about 1 h, slowly heat to 60-65°C after the addition is complete, and react for 2 h. Extract with dichloroethane and separate the layers, and concentrate the organic phase to obtain compound IV (165.1 g, 95%) with a yield of 92.2%.

[0182] The yield of compound IV synthesized from compound VI-3 was 75.7%. The synthesis process from compound IV to compound I was carried out according to the method of Example 1. Combined with the yield of compound I synthesized from compound IV in Example 1, the total yield of compound I synthesized from compound VI-2 was calculated to be 60.4%;

[0183] Example 4

[0184] The method of Example 1 was followed, except that the cyclization reagent was replaced with phthalic anhydride when synthesizing Compound III. The synthesis method of the compound is as follows.

[0185] Preparation of 2-(5-amino-2-fluoro-4-methylphenyl)isoindolin-1-one (III)

[0186] Compound V (1 mol, 175.4 g), dichloroethane (526.2 g), and phthalic anhydride (1.05 mol, 157.1 g) were added to a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, a water separator, and a condenser. The mixture was heated to reflux under stirring and the water was separated for 6 h. The mixture was cooled to 0°C and filtered to obtain a condensation product (322.7 g, 97%), which was used directly in the next step.

[0187] The condensation product (322.7 g, 97%) and acetic acid (877 g) obtained in the previous step were added to a four-necked reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser tube, and the temperature was raised to 110-115°C under stirring, and zinc powder (11 mol, 734 g) was added in 9-10 batches, and the reaction was kept warm for 8 hours. The mixture was filtered while hot, and the filtrate was concentrated to recover acetic acid. The residue was extracted with dichloroethane and water and concentrated again to obtain compound III (240.8 g, 96%) with a yield of 90.2%.

[0188] The total yield of compound I synthesized in this example is 55.3%.

[0189] Example 5

[0190] The method of Example 1 was followed, except that the alkylating agent was replaced with 2,2,2-trifluoroiodoethane when synthesizing Compound I. The synthesis method of the compound is as follows.

[0191] Preparation of 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one (Compound I)

[0192] Compound II-1 (2-(2-fluoro-4-methyl-5-thiocyanatophenyl)isoindolin-1-one, 1 mol, 307.6 g), potassium carbonate (1.9 mol, 265.3 g), DMF 922.7 g and 2,2,2-trifluoroiodoethane (1.1 mol, 235.6 g) were added to a four-necked reaction bottle equipped with a mechanical stirrer, a thermometer, and a condenser. The temperature was raised to 70-75°C under nitrogen protection and the reaction was kept warm for 6 hours. The temperature was lowered to 0°C, filtered, and the filtrate was adjusted to a neutral pH with dichloroethane and water and hydrochloric acid. The filtrate was extracted and separated into layers. The organic phase was concentrated to obtain the alkylation product (361 g, 93.5%), which was directly used in the next step;

[0193] In a four-mouth reaction flask equipped with a mechanical stirrer, a thermometer, and a condenser, 922.7 g of dichloroethane, 4-hydroxy-2,2,6,6-tetramethylpiperidinyl nitroxide free radical (6.2 g), and ferric nitrate (15.4 g) were first added in sequence, and then the alkylation reaction product (361 g, 93.5%) obtained in the previous step was added under stirring, and finally the air flow meter was turned on, the flow rate was adjusted to 200-240 mL / min, the temperature was raised to 55-60°C, and the reaction was kept warm for 5 hours. The temperature was lowered to room temperature, water was added for extraction and stratification, the organic phase was adjusted to a neutral pH with hydrochloric acid, the stratification was carried out, and the organic phase was concentrated to obtain compound I (360.8 g, 92.9%), with a yield of 90.3%.

[0194] The total yield of compound I synthesized in this example is 63.2%.

[0195] It can be seen from the yield data of Examples 1-5 that the total yield of compound I prepared by the technical scheme of the present invention using compound VI-1, VI-2 or VI-3 as the starting material is 56.5-64.5%, which is higher than the yield of compound I synthesized by CN115701423, and the synthesis process of the scheme is simple and the post-treatment is convenient. Compared with the prior art patents CN 110028431, CN111978225, CN111978226, CN 112166105, and CN115701423, since the technical scheme of the present invention synthesizes the final product compound I through the intermediate compound III, it does not involve the thiolation of chlorosulfonic acid and the oxidation of hydrogen peroxide or m-CPBA, thereby avoiding the generation of a large amount of three wastes during the reaction process, and the raw materials used in the present invention are low in price, which embodies the beneficial effects of high reaction yield, low production of three wastes and low comprehensive cost.

[0196] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing a sulfoxide compound, the method comprising: (1) subjecting compound III to diazotization reaction and coupling reaction to obtain compound II; (2) subjecting the compound II in step (1) to an alkylation reaction and an oxidation reaction to obtain a compound I; Wherein, R3 is selected from H, cyano, C3-C6 acyl or C2-C4 thioester.

2. The method according to claim 1, wherein: In step (1), the compound III is first subjected to a diazotization reaction with an inorganic acid A and a diazotizing agent in the presence of a solvent A, and then subjected to a coupling reaction with a sulfur-containing coupling agent in the presence of a catalyst A and a solvent A to obtain a compound II; Preferably, the solvent A is selected from C1-C 10 The organic solvent is further preferably at least one of acetonitrile, tetrahydrofuran, acetone, methyl isopropyl ketone, ethyl acetate, methyl acetate, dichloromethane, dichloroethane, dioxane, cyclohexane, n-hexane and toluene, more preferably toluene; Preferably, the inorganic acid A is selected from at least one of hydrochloric acid, phosphoric acid and sulfuric acid, more preferably hydrochloric acid; Preferably, the diazotizing agent is selected from nitrite and / or nitrite ester compounds, preferably at least one of sodium nitrite, potassium nitrite, ethyl nitrite, methyl nitrite, isopropyl nitrite and butyl nitrite, more preferably sodium nitrite; Preferably, the catalyst A is at least one selected from the group consisting of iron, copper, ferrous chloride, ferrocene, zinc, nickel chloride and nickel, preferably copper; Preferably, the sulfur-containing coupling reagent is selected from at least one of thiocyanate, hydrogen sulfide, sulfide and C1-C6 organic acid salt, and is further preferably selected from at least one of sodium thiocyanate, ammonium thiocyanate, potassium thiocyanate, mercuric thiocyanate, cuprous thiocyanate, copper thiocyanate, silver thiocyanate, cobalt thiocyanate, ferric thiocyanate, sodium hydrogen sulfide, potassium hydrogen sulfide, sodium sulfide, potassium sulfide, potassium ethyl xanthate, potassium thiopropionate, sodium thiopropionate, sodium thiopivalate, potassium thiopivalate, sodium 2,2-dimethylthiobutyrate, potassium 2,2-dimethylthiobutyrate and potassium 3,3-dimethylthiobutyrate, and is more preferably sodium thiocyanate.

3. The method according to any one of claims 1 and 2, wherein: In step (2), the compound II undergoes an alkylation reaction with an alkylating agent in the presence of a base A and a solvent B, and then is contacted with a catalyst A1 and / or an oxidant in the presence of a solvent C to undergo an oxidation reaction to obtain a compound I; Preferably, the base A is selected from at least one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, triethylamine, tri-n-butylamine, pyridine, morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 3,4-dimethylaminopyridine, more preferably potassium carbonate; Preferably, the solvent B is selected from C1-C 10 The organic solvent is further preferably at least one of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dioxane, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, dimethyl carbonate, cyclohexane, acetone, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, more preferably N,N-dimethylformamide; Preferably, the alkylating agent is selected from trifluoroethyl sulfonate, halogenated trifluoroiodoethane, more preferably 2,2,2-trifluoroethyl methyl sulfonate, 2,2,2-trifluoroethyl benzene sulfonate, 2,2,2-trifluoroethyl-4-toluene sulfonate, 2,2,2-trifluoroethyl trifluoromethyl sulfonate, 1,1,1-trifluoroiodoethane, 1,1,1-trifluorochloroethane, 1,1,1-trifluorobromoethane, more preferably at least one of 2,2,2-trifluoroethyl-4-toluene sulfonate and 1,1,1-trifluoroiodoethane; Preferably, the alkylation reaction is carried out in a nitrogen atmosphere; Preferably, the solvent C is selected from C1-C 10 The organic solvent is further preferably at least one of dichloromethane, ethylene dichloride, chloroform, tetrahydrofuran, dioxane, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, cyclohexane, acetone, toluene, xylene, N,N-dimethylacetamide and N-methylpyrrolidone, more preferably ethylene dichloride and / or toluene; Preferably, the catalyst A1 is selected from at least one of TEMPO, a derivative of TEMPO, a nitrosyl oxidation catalyst Nor-AZADO and 1-Me-AZADO, more preferably TEMPO and / or 4-OH-TEMPO. Preferably, the oxidant is selected from at least one of air, oxygen, manganese oxides or manganates with a valence state of 4-7, iron halides, iron nitrates, sodium tungstate, potassium or sodium salts of hypohalous acids, potassium or sodium salts of halous acids, potassium or sodium salts of halogen acids, potassium or sodium salts of perhalic acids, iodobenzene diacetate, performic acid, peracetic acid, peroxydichloroacetic acid, peroxydifluoroacetic acid, peroxytrifluoroacetic acid, potassium or sodium persulfate, ammonium persulfate, sodium or potassium nitrite, and benzene compounds containing nitro groups, and more preferably air and / or nitrates.

4. The method according to claim 2, wherein: The inorganic acid A is selected from an aqueous solution of an acid, and its concentration is 10-30wt%, preferably 15-25wt%; Preferably, the molar ratio of the inorganic acid A, the diazotizing agent, the catalyst A and the sulfur-containing coupling agent to the compound III is 2-6: 1.001-1.2: 0.005-0.2: 1.001-1.5: 1, preferably 2.5-4: 1.01-1.1：0.01-0.1：1.05-1.2：1； Preferably, the mass ratio of the solvent A to the compound III is 0.5-5:1, preferably 2.5-3.5:1; Preferably, the temperature of the diazotization reaction is -10 to 8°C, more preferably -2 to 5°C; Preferably, the coupling reaction temperature is -10 to 10°C, more preferably -5 to 5°C; Preferably, the reaction time of the diazotization reaction is 0.5-5 h, more preferably 1.5-4 h; the reaction time of the coupling reaction is 0.5-6 h, more preferably 1-3.5 h.

5. The method according to any one of claims 3 and 4, wherein: The molar ratio of the base A, the alkylating agent and the compound II is 1.01-3:1.001-1.5:1, preferably 1.1-2.5:1.01-1.3:1; Preferably, the mass ratio of the solvent B to the compound II is 0.5-5:1, preferably 2-4:1; Preferably, the temperature of the alkylation reaction is 0-120°C, more preferably 20-80°C; Preferably, the mass ratio of the solvent C to the compound II is 1-6:1, more preferably 2-4.5:1; Preferably, the temperature of the oxidation reaction is -10°C to 80°C, more preferably 0-65°C; Preferably, the mass ratio of the catalyst A1 to the compound II is 0.0005-0.2, more preferably 0.001-0.05; Preferably, the molar ratio of the oxidant to compound II is 0.005-1.5:1, more preferably 0.01-1.1:1; preferably, when the oxidant is selected from air or a combination of air, the air flow rate is 5-1000 mL / min, more preferably 80-500 mL / min; Preferably, the reaction time of the alkylation reaction is 0.5-10h, more preferably 2-7h; Preferably, the reaction time of the oxidation reaction is 0.5-10 h, more preferably 1.5-6 h.

6. The method according to any one of claims 1 to 5, wherein: The compound III is prepared by a condensation reaction of the compound IV and a cyclization agent in the presence of a solvent D, followed by an intramolecular cyclization reaction under the action of a base B, or a condensation reaction of the compound IV and a cyclization agent in the presence of a solvent D; and finally a reduction reaction in the presence of a solvent F, a catalyst B and / or a reducing agent; Preferably, the cyclization agent is selected from phthalic anhydride or 2-chloromethylbenzoyl chloride; Preferably, the base B is selected from sodium carbonate, potassium carbonate, sodium (or potassium) salt of C1-C4 alcohol (including solution), sodium hydroxide, potassium hydroxide, sodium hydride, triethylamine, tri-n-butylamine, pyridine, morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, sodium hydride, more preferably sodium carbonate, sodium methoxide; Preferably, the solvent D is selected from C1-C 10 The organic solvent is further preferably at least one of dichloromethane, dichloroethane, chloroform, cyclohexane, n-hexane, tetrahydrofuran, dioxane, toluene, benzene, chlorobenzene, dichlorobenzene and xylene, more preferably dichloroethane and / or toluene; Preferably, the catalyst B is selected from Raney nickel, carbon containing 1-10wt% palladium, carbon containing 1-10wt% platinum, zinc powder, iron powder or copper powder, preferably Raney nickel; Preferably, the reducing agent is at least one of hydrogen, sodium cyanoborohydride, borane dimethyl sulfide, sodium borohydride, diborane, lithium aluminum hydride, zinc powder, iron powder, and aluminum powder, more preferably hydrogen or sodium borohydride; Preferably, the solvent F is selected from at least one of methanol, ethanol, propanol, n-butanol, isopropanol, tetrahydrofuran, ethylene dichloride, dichloromethane, dimethyl ketone, cyclohexanol, ethylene glycol, carbon tetrachloride, dioxane, acetic acid, oxalic acid, malonic acid, benzene, toluene, xylene, halogenated benzene, and trifluorotoluene; more preferably, ethylene dichloride and / or methanol, tetrahydrofuran.

7. The method according to claim 6, wherein: The mass ratio of the solvent D to the compound IV is 1-6:1, preferably 2.5-4:1; Preferably, in the condensation reaction, the molar ratio of phthalic anhydride and / or 2-chloromethylbenzoyl chloride to compound IV is 1.001-1.2:1, more preferably 1.005-1.1:1; Preferably, the temperature of the condensation reaction is 60-150°C, more preferably 80-115°C.

8. The method according to any one of claims 6 and 7, wherein: The molar ratio of the base B to the compound IV is 0.5-1.5:1, more preferably 0.6-1.1:1; Preferably, the reaction time of the condensation reaction is 0.5-8h, more preferably 2-6h; Preferably, the temperature of the ring-closing reaction is -10°C to 80°C, more preferably 0-60°C; Preferably, the reaction time of the ring-closing reaction is 0.5-8h, more preferably 1-6h; Preferably, the mass ratio of the catalyst B to the compound IV is 0.005-0.1:1, more preferably 0.01-0.05:1; Preferably, the mass ratio of the solvent F to the compound IV is 1-8:1, more preferably 2.5-6:1; Preferably, the pressure of the hydrogen is 0.5-4.5 MPa, more preferably 1-2.5 MPa; or the molar ratio of the reducing agent to the compound IV is 1.001-15:1, more preferably 2.01-12:1; Preferably, the temperature of the reduction reaction is 0-100°C, more preferably 20-80°C; Preferably, the reaction time of the reduction reaction is 1-15 h, more preferably 3-10 h.

9. The method according to any one of claims 6 to 8, wherein: The compound IV is prepared by subjecting the compound V to an acylation reaction, an amination reaction, or by subjecting the compound V to a hydrolysis reaction in a base C solution, followed by a degradation reaction in the presence of a solvent J, a halogenating agent, and a base D; Wherein, R1 is selected from -CN, -CX3, -COOR; Wherein, R is selected from one of H or C1-C6 alkyl; X is selected from halogen; Preferably, the process of the acylation reaction is that when R1 is selected from -CX3, compound V is subjected to an acylation reaction with an organic acid under the action of a Lewis acid to obtain an acylated product, or when R1 is selected from -COOR and R is H, compound V is subjected to an acylation reaction with an acylating agent in the presence of a solvent G and a catalyst C; Preferably, the process of the amination reaction is that the product of the acylation reaction is subjected to an amination reaction with an amination reagent in the presence of a solvent G; Preferably, the Lewis acid is selected from at least one of tin dichloride, tin tetrachloride, ferric chloride, ferrous chloride, zinc dichloride, aluminum chloride, copper chloride, copper bromide, copper iodide and boron trifluoride, more preferably ferric chloride and / or aluminum chloride; Preferably, the organic acid is selected from at least one of formic acid, acetic acid, oxalic acid, propionic acid and malonic acid, more preferably oxalic acid; Preferably, the catalyst C is N,N-dimethylformamide; Preferably, the acylating agent is selected from at least one of thionyl chloride, oxalyl chloride, phosgene and phosphorus trichloride, more preferably thionyl chloride; Preferably, the solvent G is selected from C1-C 10 The organic solvent is further preferably at least one of dichloroethane, toluene, dichloromethane, xylene, cyclohexane and n-hexane, more preferably dichloroethane; Preferably, the aminating agent is selected from ammonia gas or ammonia water, more preferably ammonia water; Preferably, the alkali C in the alkali C solution is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate, more preferably sodium carbonate; Preferably, the solvent J is selected from at least one of water, ethanol, methanol, isopropanol, cyclohexane, ethylene dichloride, tetrahydrofuran, dioxane, toluene, benzene, xylene, halogenated benzene, methyl acetate, ethyl acetate, methyl isopropyl ketone, dimethyl ketone and di-tert-butyl ketone, more preferably water; Preferably, the halogenating agent is selected from at least one of chlorine, bromine, iodine, halogenated succinimide, trichloroisocyanuric acid, tribromoisocyanuric acid, sodium hypochlorite, sodium hypobromite and sodium hypoiodite, more preferably at least one of bromine, chlorine, sodium hypochlorite and sodium hypobromite; Preferably, the base D is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide, more preferably sodium hydroxide.

10. The method according to claim 9, wherein: The molar ratio of the acylating agent to compound V is 1.001-1.5:1, more preferably 1.01-1.1:1; Preferably, the molar ratio of the Lewis acid to the compound V is 0.005-1.2:1, more preferably 0.01-1.1:1; Preferably, the molar ratio of the organic acid to the compound V is 0.51-1.2:1; more preferably 0.55-1.05; Preferably, the mass ratio of the solvent G to the compound V is 0.5-5:1, more preferably 2-3.5:1; Preferably, the mass ratio of the catalyst C to the compound V is 0.001-0.01:1, more preferably 0.01-0.03:1; Preferably, the mass ratio of the solvent J to the compound V is 2-8:1, more preferably 3-5:1; Preferably, the molar ratio of the aminating agent to compound V is 1.01-4.0:1, more preferably 1.5-2.5:1; Preferably, the temperature of the acylation reaction is 20-180°C, more preferably 80-150°C; Preferably, the temperature of the amination reaction is -10 to 10°C, more preferably -5 to 5°C; Preferably, the concentration of the base C solution is 5-50%, more preferably 10-30%; Preferably, the mass ratio of the alkaline C solution to the compound V is 0.5-6:1, more preferably 1-3:1; Preferably, the temperature of the hydrolysis reaction is 0-80°C, more preferably 55-60°C; Preferably, the ratio of the solvent J to the compound V is 0.5-8:1, more preferably 3-6:1; Preferably, the molar ratio of the halogenating agent to compound V is 1.01-3.5:1, preferably 1.05-2.5:1; Preferably, the concentration of the base D solution is 10-50%, more preferably 15-30%; the molar ratio of the base D to the compound V is 1.1-4.0:1, preferably 1.5-2.6:1; Preferably, the temperature of the degradation reaction is -10 to 100°C, more preferably -5 to 80°C; Preferably, the amination reaction time is 0.5-5h, more preferably 1.5-3h; Preferably, the degradation reaction time is 1-10 h, more preferably 3-7 h.

11. The method according to any one of claims 9 and 10, wherein: The compound V is prepared by a substitution reaction of the compound VI with a substitution reagent in the presence of a base E and a solvent K, a deesterification hydrolysis reaction with an inorganic acid B in the presence of a solvent L, and finally a decarboxylation reaction in the presence of a catalyst D and a solvent Q; Wherein, R1 is selected from -CN, -CX3, -COOR; R2 is selected from halogen; Wherein, is selected from one of H or C1-C6 alkyl; X is selected from halogen; Preferably, the base E is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and sodium / potassium salt of C1-C4 alkyl alcohol, more preferably potassium carbonate; Preferably, the solvent K is selected from C1-C 10 The organic solvent is further preferably selected from at least one of tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and sulfolane, more preferably N,N-dimethylformamide; Preferably, the substitution reagent is selected from at least one of dimethyl malonate, diethyl malonate, dipropyl malonate, dibutyl malonate, diisopropyl malonate, diisobutyl malonate, di-tert-butyl malonate, methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, butyl cyanoacetate, isopropyl cyanoacetate, tert-butyl cyanoacetate, isobutyl cyanoacetate and isoamyl cyanoacetate, more preferably methyl cyanoacetate and dimethyl malonate; Preferably, the solvent L is selected from at least one of formic acid, acetic acid, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene and water, more preferably acetic acid; Preferably, the inorganic acid B is selected from at least one of hydrochloric acid, sulfuric acid and phosphoric acid, more preferably sulfuric acid; Preferably, the catalyst D is selected from one of silver halide, silver carbonate, silver acetate, silver nitrate, nickel chloride, nickel acetate, manganese acetate, palladium acetate, palladium chloride, palladium carbonate, copper chloride and iron chloride, preferably silver acetate and / or silver carbonate; Preferably, the solvent Q is selected from at least one of tetrahydrofuran, acetonitrile, dioxane, ethylene dichloride, ethyl acetate, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and sulfolane, more preferably dioxane and / or tetrahydrofuran.

12. The method according to claim 11, wherein: The molar ratio of the base E, the substitution agent and the compound VI is 1.01-1.5:1.001-1.5:1, preferably 1.05-1.2:1.05-1.2:1; Preferably, the mass ratio of the solvent K to the compound VI is 0.5-5:1, preferably 1-3.0:1; Preferably, the temperature of the substitution reaction is 0-100°C, preferably 20-60°C; Preferably, the molar ratio of the inorganic acid B to the compound VI is 1-4:1, more preferably 1.5-3:1; Preferably, the inorganic acid B is selected from an aqueous solution of an acid, and its concentration is 20-90wt%, preferably 36-80wt%; Preferably, the mass ratio of the solvent L to the compound VI is 0.5-5:1, more preferably 1-3.5:1; Preferably, the temperature of the deesterification hydrolysis reaction is 50-110°C, preferably 90-95°C; Preferably, the deesterification hydrolysis reaction time is 1-15h, preferably 6-11h; Preferably, the molar ratio of the catalyst D to the compound VI is 0.001-0.05:1, more preferably 0.003-0.015:1; Preferably, the mass ratio of the solvent Q to the compound VI is 0.5-4:1, preferably 1-2.5:1; Preferably, the temperature of the decarboxylation reaction is 20-150°C, preferably 40-60°C; Preferably, the substitution reaction time is 0.5-12h, more preferably 1.5-8h; Preferably, the reaction time of the decarboxylation reaction is 0.5-10 h, preferably 1.5-8 h.

13. An aniline compound, characterized in that: The compound has a structure shown in Formula III:

14. A method for preparing an aniline compound, characterized in that: The method includes: Compound IV is contacted with a cyclization reagent to undergo a cyclization reaction to obtain the obtained compound; Wherein, the compound IV corresponds to the same definition as described in any one of claims 6-9; the cyclization reagent has the same definition as described in claim 6.

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