Preparation method of trifluoroethyl sulfide (sulfoxide) substituted benzene compounds and intermediates thereof

Abstract

The present invention relates to a method for preparing a trifluoroethyl sulfide substituted benzene compound and an intermediate used in the method. The method comprises the following steps: step 1): subjecting a compound of general formula VII to a condensation reaction with a compound of general formula VI to obtain a compound of general formula V; step 2): subjecting the compound of general formula V to a sulfonation reaction to obtain a compound of general formula IV; step 3): subjecting the compound of general formula IV to a reduction reaction to obtain a compound of general formula III; step 4): subjecting the compound of general formula III to an alkylation reaction to obtain a compound of general formula II. The present invention also relates to a method for preparing a trifluoroethyl sulfoxide substituted benzene compound, comprising the step of subjecting the compound of general formula II to an oxidation reaction to obtain a compound of general formula I. The method of the present invention has the advantages of simplicity, high efficiency, high yield, reduced cost, and the like.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a preparation method of a trifluoroethyl sulfide (sulfoxide) substituted benzene compound and an intermediate used in the method. Background Art

[0002] Trifluoroethyl sulfide (sulfoxide) substituted benzene compounds are a new type of highly efficient acaricide. Chinese patent CN110028431A discloses trifluoroethyl sulfide (sulfoxide) substituted benzene compounds as shown in general formula I and / or general formula II, which show excellent acaricidal activity against Tetranychus cinnabarinus. The patent disclosure also records the synthesis route and method of the compounds, and the specific reaction formula is shown in route 1 (wherein G=R7=Cl or Br). In route 1, substituted aniline (compound of general formula D) is used as the starting reactant, and an ortho-halogenated methylene halide compound (compound of general formula C) is used to prepare a compound of general formula B, which is then subjected to an oxidation reaction to prepare a compound of general formula A, and finally subjected to an intramolecular cyclization reaction to prepare a compound of general formula I; or, the compound of general formula B is first subjected to an intramolecular cyclization reaction to prepare a compound of general formula II, and then subjected to an oxidation reaction to prepare a compound of general formula I.

[0003]

[0004]

[0005] Route 1

[0006] WO2010100189, US2012053052, JP2012519662, EP2403837, CN102341376, WO2013092350, WO2013157229, WO2007131680, WO2015036377, WO2013030319, WO2013030262, WO2013030338, WO2018015852, WO2014202510, WO2014202505 or WO2015004028 disclose a synthetic route and method for substituted aniline (compound of general formula D), and the specific reaction formula is shown in Scheme 2. In route 2, substituted aniline (compound of formula VII) is used as the starting reactant, and first an acylation reaction is performed to obtain a compound of formula J, and then sulfonation is performed with chlorosulfonic acid to obtain a compound of formula H, and then a reduction reaction is performed to obtain a compound of formula F and / or G, and then a strong base hydrolysis reaction is performed to obtain a compound of formula E, and finally an alkylation reaction is performed to obtain a compound of formula D.

[0007]

[0008]

[0009]

[0010] Route 2

[0011] In the above method, the steps are cumbersome and the reaction route is complicated, which makes the final product yield low and is not conducive to large-scale production. Therefore, technicians have been committed to continuously researching and developing new, more advanced and reasonable, and more environmentally friendly preparation methods, so as to obtain efficient and safe trifluoroethyl sulfide (sulfoxide) substituted benzene acaricides with better quality and lower price. Summary of the invention

[0012] Technical issues

[0013] The trifluoroethyl sulfide (sulfoxide) substituted benzene compounds involved in the present invention are a new type of highly efficient and safe acaricide. In order to find a method suitable for large-scale industrial production of trifluoroethyl sulfide (sulfoxide) substituted benzene compounds, the inventors have conducted a new exploration of its traditional preparation process.

[0014] In the process of studying a new preparation method, the inventors unexpectedly found that the preparation process of the present invention uses substituted aniline (compound of general formula VII) as a raw material, and through condensation, sulfonation, reduction, alkylation, oxidation, a total of five steps of reaction, trifluoroethyl sulfide (sulfoxide) substituted benzene compounds of general formula I and / or general formula II can be prepared in high yield, and are suitable for large-scale industrial production.

[0015] Therefore, the present invention provides a new method for large-scale preparation of trifluoroethyl sulfide (sulfoxide) substituted benzene compounds represented by general formula I and / or general formula II.

[0016] Technical Solution

[0017] The object of the present invention is to provide a method for preparing trifluoroethyl sulfide (sulfoxide) substituted benzene compounds which is suitable for large-scale industrial production.

[0018] According to a first aspect of the present invention, there is provided a method for preparing a trifluoroethyl sulfide substituted benzene compound represented by general formula II, comprising the following steps:

[0019] Step 1): subjecting the compound of formula VII to a condensation reaction with the compound of formula VI to obtain a compound of formula V;

[0020] Step 2): subjecting the compound of formula V to a sulfonation reaction to obtain a compound of formula IV;

[0021] Step 3): The compound of formula IV undergoes a reduction reaction to obtain a compound of formula III;

[0022] Step 4): The compound of formula III undergoes an alkylation reaction to obtain a compound of formula II;

[0023]

[0024] in:

[0025] R1 and R2 are each independently selected from hydrogen, halogen, cyano, C1-C 10 Alkyl or C1-C 10 Haloalkyl; preferably hydrogen, halogen, cyano, C1-C6 alkyl or C1-C6 haloalkyl; more preferably hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; further more preferably hydrogen, fluorine, chlorine, bromine, cyano or methyl; most preferably R1 is fluorine, and R2 is selected from methyl or chlorine;

[0026] R3, R4, R5 and R6 are each independently selected from hydrogen, halogen, cyano, nitro, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy or C1-C 10 haloalkoxy; preferably hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; more preferably hydrogen, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy; further more preferably hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy; most preferably, R3 and R6 are hydrogen, and R4 and R5 are each independently selected from hydrogen or fluorine;

[0027] R7 is selected from hydrogen, acetyl or G;

[0028] .

[0029] According to a second aspect of the present invention, there is provided a method for preparing a trifluoroethyl sulfoxide substituted benzene compound represented by general formula I, comprising the following steps:

[0030] 1') preparing a compound of formula II according to the method described in the first aspect above;

[0031] 2') subjecting the compound of formula II to an oxidation reaction to obtain a compound of formula I;

[0032]

[0033] Wherein, R1 to R6 are as defined in the first aspect.

[0034] For the first and second aspects above, preferably, the definitions of R1, R2, R3, R4, R5, R6 and R7 can be as shown in Table 1:

[0035] Table 1

[0036]

[0037]

[0038] Preferably,

[0039] In step 1), the compound of formula VII and the compound of formula VI are dissolved in solvent A, and reacted at a temperature between 0°C and the boiling point of the solvent A to obtain a compound of formula V. Preferably, the molar ratio of the compound of formula VII to the compound of formula VI is 1:1-3, more preferably 1:1-2, and even more preferably 1:1-1.5, for example 1:1-1.1;

[0040] In step 2), the compound of formula V reacts with a sulfonating agent at a temperature of -10°C to 200°C, preferably -10°C to 160°C, to obtain a compound of formula IV, wherein the molar ratio of the compound of formula V to the sulfonating agent is preferably 1:1-100, more preferably 1:1-80;

[0041] In step 3), the compound of formula IV is reacted with a reducing agent at a temperature of 0°C to 200°C, preferably 0°C to 150°C, more preferably 0°C to 130°C, for example 0°C to 120°C to obtain a compound of formula III, wherein the reducing agent is preferably composed of a transition metal and an acid, the acid is selected from an organic acid or an inorganic acid, and the molar ratio of the compound of formula IV to the transition metal and the acid is 1:1-50:1-100, more preferably 1:1-30:1-100, further more preferably 1:1-20:1-80, for example 1:5-15:5-60;

[0042] In step 4), the compound of formula III is reacted with a halogenating agent or a sulfonate and a base in a solvent B at a temperature ranging from 0°C to the boiling point of the solvent B to obtain a compound of formula II. Preferably, the molar ratio of the compound of formula III to the halogenating agent or the sulfonate and the base is 1:1-5:1-5, more preferably 1:1-4:1-4, and further more preferably 1:1-4:1-3, for example 1:1-3:1-2.

[0043] Preferably, in step 2'), the compound of formula II is reacted with an oxidizing agent in a solvent C at a temperature ranging from -10°C to the boiling point of the solvent C to obtain a compound of formula I. Preferably, the molar ratio of the compound of formula II to the oxidizing agent is 1:1-10, more preferably 1:1-8, further more preferably 1:1-6, for example 1:1-5.

[0044] Preferably, the solvent A is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, ethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dimethyl ether, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butyl ketone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, acetonitrile, tetrahydrofuran, dioxane, N, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.

[0045] Preferably, the sulfonating agent is selected from one or more of chlorosulfonic acid, concentrated sulfuric acid, oleum, sulfur trioxide and sulfur monochloride.

[0046] Preferably, the transition metal is selected from zinc, iron, copper or nickel or a mixture of zinc, iron, copper and nickel in any proportion; the acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and nitric acid.

[0047] Preferably, the halogenating agent is selected from trifluoroiodoethane; and the sulfonate is selected from one or more of 2,2,2-trifluoroethyl methanesulfonate, 2,2,2-trifluoroethyl benzenesulfonate or 2,2,2-trifluoroethyl p-toluenesulfonate.

[0048] Preferably, the base is selected from one or more of trimethylamine, triethylamine, pyridine, DBU, N, N-diisopropylmethylamine, N, N-diisopropylethylamine, 4-dimethylaminopyridine, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide or sodium tert-butoxide.

[0049] Preferably, the solvent B is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dimethyl ether, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butyl ketone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, water, acetonitrile, tetrahydrofuran, dioxane, N, N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.

[0050] Preferably, the oxidizing agent is selected from one or more of meta-chloroperbenzoic acid, hydrogen peroxide or sodium (meta)periodate.

[0051] Preferably, the solvent C is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dimethyl ether, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butyl ketone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, water, acetonitrile, tetrahydrofuran, dioxane, N, N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.

[0052] Preferably, in the reaction of step 3), red phosphorus and iodine are further added.

[0053] More preferably, the molar ratio of the compound of formula IV to red phosphorus and iodine is 1:1-10:0.02-0.2, more preferably 1:2-8:0.05-0.15, and further preferably 1:2-6:0.05-0.1.

[0054] According to the third aspect of the present invention, there is provided a compound having a structure shown in general formula III:

[0055]

[0056] in:

[0057] R1 to R7 are as defined above.

[0058] According to a fourth aspect of the present invention, there is provided a compound having a structure shown in general formula IV:

[0059]

[0060] in:

[0061] R1 to R6 are as defined above.

[0062] In the definitions of the groups in the above-mentioned synthesis methods and compounds of the general formula, the terms used are generally defined as follows:

[0063] Halogen means fluorine, chlorine, bromine or iodine;

[0064] Alkyl refers to straight-chain or branched alkyl groups, such as methyl, ethyl, n-propyl, isopropyl or the different butyl isomers;

[0065] Haloalkyl refers to a straight or branched chain alkyl group, on which the hydrogen atoms may be partially or completely replaced by halogen, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, etc.;

[0066] Alkoxy refers to a straight or branched chain alkyl group connected to the structure via an oxygen atom bond, such as methoxy, ethoxy, tert-butoxy, etc.;

[0067] The haloalkoxy group refers to an alkoxy group in which the hydrogen atoms may be partially or completely replaced by halogens, for example, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, trifluoroethoxy and the like.

[0068] Beneficial Effects

[0069] Compared with the prior art, the present invention has the following advantages:

[0070] 1. Short synthetic route: The prior art uses substituted aniline (compound of formula VII) as the starting reactant, and requires 7 steps of reaction to prepare compound of formula II, and 8 steps of reaction to prepare compound of formula I; while the present invention also uses substituted aniline (compound of formula VII) as the starting reactant, and only 4 steps of reaction are required to prepare compound of formula II, and only 5 steps of reaction are required to prepare compound of formula I.

[0071] 2. The yield of each step is high: the yield of step 1) of the method of the present invention (preparing the compound of formula V from the compound of formula VII) is above 90% (the highest in the embodiment of the present invention is 96%); the yield of step 2) (preparing the compound of formula IV from the compound of formula V) is above 85% (the highest in the embodiment of the present invention is 94%); the yield of step 3) (preparing the compound of formula III from the compound of formula IV) is above 80% (the highest in the embodiment of the present invention is 96%); the yield of step 4) (preparing the compound of formula II from the compound of formula III) is above 80% (the highest in the embodiment of the present invention is 94.6%); the yield of step 2') (preparing the compound of formula I from the compound of formula II) is above 85% (the highest in the embodiment of the present invention is 94.2%).

[0072] 3. In the reduction reaction of the compound of formula IV to prepare the compound of formula III, the reduction of the sulfonyl chloride group (Part A) and the reduction of the carbonyl group (Part B) are creatively and successfully achieved in one step. This method has the advantages of simplicity, high efficiency, high yield, and reduced cost.

[0073] DETAILED DESCRIPTION

[0074] The following examples are used to illustrate the preparation method of trifluoroethyl sulfide (sulfoxide) substituted benzene compounds represented by general formula I and / or general formula II of the present invention in detail, but are not intended to limit the present invention. Various changes and modifications can be made within the scope defined by the claims of the present invention.

[0075] Example 1: Preparation of 2-(2-fluoro-4-methylphenyl)isoindole-1,3-dione

[0076]

[0077] Add 2-fluoro-4-methylaniline (10 g, 0.08 mol), 250 mL toluene and phthalic anhydride (12.4 g, 0.084 mol) to a 500 mL reaction bottle, stir and reflux to separate water. After 8 hours of reaction, the reaction solution cooled to room temperature. The reaction solution was concentrated to dryness, extracted with 200 mL ethyl acetate and 200 mL water, washed with saturated sodium bicarbonate solution and saturated brine in sequence, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to obtain 20 g of white solid 2-(2-fluoro-4-methylphenyl)isoindole-1,3-dione, with a HPLC quantitative content of 98.2%, corresponding to a yield of 96%.

[0078] Example 2: Preparation of 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride

[0079]

[0080] Chlorosulfonic acid (411 g, 3.55 mol) was added to a 500 mL three-necked flask, cooled to 0~5°C, and 2-(2-fluoro-4-methylphenyl)isoindole-1,3-dione (15 g, 0.059 mol) was added in batches, and the reaction temperature was controlled not to exceed 5°C. After 30 minutes of reaction, the reaction solution was slowly dripped into ice water, a white solid was precipitated and filtered, and the filter cake was dried to obtain 20 g of white solid 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride, with a HPLC quantitative content of 98.5%, corresponding to a yield of 94%.

[0081] Example 3: Preparation of 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride

[0082]

[0083] Chlorosulfonic acid (35.4 g, 303.8 mmol) was added to a 100 mL three-necked flask, and 2-(2-fluoro-4-methylphenyl)isoindole-1,3-dione (1 g, 3.9 mmol) was added in batches, and then the temperature was raised to 150°C. After reacting for 10 minutes, the reaction solution was cooled to room temperature. The reaction solution was slowly dripped into ice water, a white solid was precipitated and filtered, and the filter cake was dried to obtain 1.24 g of white solid 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride, with a HPLC quantitative content of 98.6%, corresponding to a yield of 88%.

[0084] Example 4: Preparation of 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride

[0085]

[0086] Chlorosulfonic acid (45.6 g, 0.39 mol) was added to a 500 mL three-necked flask, cooled to 0~5°C, and 2-(2-fluoro-4-methylphenyl)isoindole-1, 3-dione (10 g, 39 mmol) was added in batches, and the reaction temperature was controlled not to exceed 10°C. The reaction temperature was then raised to 30°C, and after 1 hour of reaction, the reaction solution was slowly dripped into ice water, a white solid was precipitated and filtered, and the filter cake was dried to obtain 12.6 g of white solid 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride, with a HPLC quantitative content of 98.3%, and a corresponding yield of 89%.

[0087] Example 5: Preparation of 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride

[0088]

[0089] Chlorosulfonic acid (22.8 g, 195 mmol) was added to a 500 mL three-necked flask, cooled to 0-5°C, and 2-(2-fluoro-4-methylphenyl)isoindole-1, 3-dione (10 g, 39 mmol) was added in batches, and the reaction temperature was controlled not to exceed 10°C. The reaction temperature was then raised to 40°C, and after reacting for 2 hours, the reaction solution was slowly dripped into ice water, a white solid was precipitated and filtered, and the filter cake was dried to obtain 12.3 g of white solid 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride, with a HPLC quantitative content of 98.1% and a corresponding yield of 87%.

[0090] Example 6: Preparation of 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride

[0091]

[0092] Chlorosulfonic acid (13.7 g, 117 mmol) was added to a 500 mL three-necked flask, cooled to 0-5°C, and 2-(2-fluoro-4-methylphenyl)isoindole-1, 3-dione (10 g, 39 mmol) was added in batches, and the reaction temperature was controlled not to exceed 10°C. The reaction temperature was then raised to 50°C, and after 3 hours of reaction, the reaction solution was slowly dripped into ice water to precipitate a white solid and filtered. The filter cake was dried to obtain 12 g of white solid 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride, with a HPLC quantitative content of 98%, and a corresponding yield of 85%.

[0093] Example 7: Preparation of 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one

[0094]

[0095] 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride (1 g, 2.8 mmol) and acetic acid (10.2 g, 170 mmol) were added to a 100 mL reaction bottle, and zinc powder (1.85 g, 28 mmol) was added under stirring. After reacting at 120 °C for 30 minutes, the reaction solution was filtered while hot. The reaction solution was rinsed with 10 mL of ethyl acetate, concentrated to dryness, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to obtain 0.73 g of 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one as a white solid, with a quantitative content of 98.7% by HPLC, and a corresponding yield of 95%.

[0096] Example 8: Preparation of 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one and S-(4-fluoro-2-methyl-5-(1-oxoisoindol-2-yl)phenyl)ethyl sulfate

[0097]

[0098] To a 100 mL reaction bottle, add 5-(1, 3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride (1 g, 2.8 mmol) and acetic acid (10.2 g, 170 mmol), and add zinc powder (1.85 g, 28 mmol) under stirring. After reacting at 120 °C for 5 hours, the reaction solution was filtered while hot. The reaction mixture was rinsed with 10 mL of ethyl acetate, concentrated to dryness, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated. Column chromatography was used to separate 0.21 g of 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one as a white solid, with a HPLC quantitative content of 98.4% and a corresponding yield of 27%; 0.52 g of S-(4-fluoro-2-methyl-5-(1-oxoisoindol-2-yl)phenyl)ethyl sulfate as a white solid, with a HPLC quantitative content of 98.8% and a corresponding yield of 58%; the total yield of 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one and S-(4-fluoro-2-methyl-5-(1-oxoisoindol-2-yl)phenyl)ethyl sulfate was 85%.

[0099] Example 9: Preparation of S-(4-fluoro-2-methyl-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate

[0100]

[0101] 5-(1,3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride (1 g, 2.8 mmol) and acetic acid (10.2 g, 170 mmol) were added to a 100 mL reaction bottle, and zinc powder (1.85 g, 28 mmol) was added under stirring. After reacting at 120 °C for 36 hours, the reaction solution was filtered while hot. The reaction solution was rinsed with 10 mL of ethyl acetate, concentrated to dryness, and extracted with 100 mL of ethyl acetate and 100 mL of water, washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to obtain 0.75 g of white solid S-(4-fluoro-2-methyl-5-(1-oxoisoindol-2-yl)phenyl)ethyl sulfate, with a HPLC quantitative content of 98.7%, and a corresponding yield of 84%.

[0102] Example 10: Preparation of 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one and S-(4-fluoro-2-methyl-5-(1-oxoisoindol-2-yl)phenyl)ethyl sulfate

[0103]

[0104]

[0105] To a 100 mL reaction bottle, add 5-(1, 3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride (1 g, 2.8 mmol), acetic acid (10.2 g, 170 mmol), and acetic anhydride (1.1 g, 11.2 mmol), and add zinc powder (1.85 g, 28 mmol) under stirring. After reacting at 120 °C for 5 hours, the reaction solution was filtered while hot. The reaction mixture was rinsed with 10 mL of ethyl acetate, concentrated to dryness, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate and concentrated. Column chromatography was used to separate 0.15 g of 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one as a white solid, with a HPLC quantitative content of 98.1% and a corresponding yield of 19%; 0.60 g of S-(4-fluoro-2-methyl-5-(1-oxoisoindol-2-yl)phenyl)ethylsulfate as a white solid, with a HPLC quantitative content of 98.2% and a corresponding yield of 67%. The total yield of 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one and S-(4-fluoro-2-methyl-5-(1-oxoisoindol-2-yl)phenyl)ethylsulfate was 86%.

[0106] Example 11: Preparation of S-(4-fluoro-2-methyl-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate

[0107]

[0108] 5-(1, 3-dioxoisoindol-2-yl)-4-fluoro-2-toluenesulfonyl chloride (1 g, 2.8 mmol), acetic acid (10.2 g, 170 mmol), acetic anhydride (1.1 g, 11.2 mmol) were added to a 100 mL reaction bottle, and zinc powder (1.85 g, 28 mmol) was added under stirring. After reacting at 120 °C for 36 hours, the reaction solution was filtered while hot. Rinse with 10 mL of ethyl acetate, concentrate the reaction solution to dryness, add 100 mL of ethyl acetate and 100 mL of water to extract, wash with saturated brine, dry the organic phase with anhydrous magnesium sulfate and concentrate, and obtain 0.75 g of white solid S-(4-fluoro-2-methyl-5-(1-oxoisoindol-2-yl)phenyl)ethyl sulfate, with a HPLC quantitative content of 98.7%, and a corresponding yield of 88%.

[0109] Example 12: Preparation of S-(4-fluoro-2-methyl-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate

[0110]

[0111] Weigh 5-(1, 3-dioxoisoindole-2-yl)-4-fluoro-2-toluenesulfonyl chloride (3 g, 8.5 mmol), acetic acid (6.9 g, 115.6 mmol), acetic anhydride (3.45 g, 33.8 mmol), red phosphorus (1.59 g, 51.3 mmol), and iodine (0.21 g, 0.8 mmol) into a 250 mL reaction bottle and heat to reflux. After 10 minutes of reaction, add zinc powder (5.55 g, 85 mmol) and acetic acid (27 g, 449.6 mmol) and continue reflux reaction for 2 hours. The reaction solution was filtered hot, the filter residue was washed with ethyl acetate, the filtrate and the washing solution were combined, concentrated under reduced pressure, the residue was extracted with 200 mL of ethyl acetate and 200 mL of water, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine in sequence, the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.6 g of white solid S-(4-fluoro-2-methyl-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate, the HPLC quantitative content was 98.9%, and the corresponding yield was 95%.

[0112] Example 13: Preparation of 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one

[0113]

[0114] Weigh S-(4-fluoro-2-methyl-5-(1-oxoisoindole-2-yl)phenyl)ethylsulfate (1 g, 3.17 mmol), 10 mL tetrahydrofuran, sodium formaldehyde sulfoxylate (0.41 g, 3.49 mmol) and add them to a 50 mL reaction bottle. Cool to 0-5°C and start adding sodium hydroxide aqueous solution (0.25 g dissolved in 5 mL water). Keep the temperature at 10°C and continue to heat for 30 minutes after the addition is complete. Add 50 mL water and 50 mL dichloromethane to the reaction solution for extraction. Concentrated hydrochloric acid (0.65 g, 6.6 mmol) was added to the aqueous phase. After the addition was complete, stirring was continued. White solid was continuously precipitated. 50 mL of dichloromethane was added for extraction. The organic phase was dried and concentrated to obtain 0.76 g of white solid 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one. The HPLC quantitative content was 98%, and the corresponding yield was 86%.

[0115] Example 14: Preparation of 2,2'-(disulfide diacetylbis(6-fluoro-4-methyl-3,1-phenylene))bis(isoindol-1-one)

[0116]

[0117] Weigh 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one (1 g, 3.66 mmol) and 10 mL tetrahydrofuran, add to a 50 mL reaction bottle, cool to 0~5°C, start dripping sodium hydroxide aqueous solution (0.29 g dissolved in 5 mL water), control the reaction temperature not to exceed 10°C, and continue to keep the temperature for 30 minutes after the addition is complete. Add 50 mL of water to the reaction solution, extract with 50 mL of dichloromethane, dry and concentrate the organic phase, and obtain 0.87 g of white solid 2, 2'-(dithiodicarboxylic acid bis(6-fluoro-4-methyl-3, 1-phenylene))bis(isoindol-1-one), with a HPLC quantitative content of 98.2%, corresponding to a yield of 85.7%.

[0118] Example 15: Preparation of 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0119]

[0120] 2-(2-Fluoro-5-mercapto-4-methylphenyl)isoindol-1-one (1 g, 3.7 mmol), potassium carbonate (1.02 g, 7.4 mmol), 10 mL N,N-dimethylformamide, sodium formaldehyde sulfoxylate (0.48 g, 4.1 mmol), and 2-iodo-1,1,1-trifluoroethane (0.85 g, 4.0 mol) were weighed and added into a 100 mL three-necked flask. After reacting at room temperature for 2 hours, 50 mL of ethyl acetate and 50 mL of water were added for extraction. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 1.18 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.7% and a corresponding yield of 91%.

[0121] Example 16: Preparation of 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0122]

[0123] 2-(2-Fluoro-5-mercapto-4-methylphenyl)isoindol-1-one (1.0 g, 3.7 mmol), potassium hydroxide (0.42 g, 7.4 mmol), 10 mL N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.48 g, 4.1 mmol), and 2-iodo-1,1,1-trifluoroethane (0.85 g, 4.1 mmol) were weighed and added into a 100 mL three-necked flask. After reacting at room temperature for 2 hours, 50 mL of ethyl acetate and 50 mL of water were added for extraction. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 1.21 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.7% and a corresponding yield of 93%.

[0124] Example 17: Preparation of 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0125]

[0126] 2-(2-Fluoro-5-mercapto-4-methylphenyl)isoindol-1-one (1 g, 3.7 mmol), potassium hydroxide (0.42 g, 7.4 mmol), sodium formaldehyde sulfoxylate (0.48 g, 4.1 mmol), 10 mL acetone, and 2-iodo-1,1,1-trifluoroethane (0.85 g, 4.0 mmol) were weighed and added into a 100 mL three-necked flask. After reacting at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was extracted with 50 mL ethyl acetate and 50 mL water. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 1.16 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one. The HPLC quantitative content was 98.7%, and the corresponding yield was 89%.

[0127] Example 18: Preparation of 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0128]

[0129] Weigh S-(4-fluoro-2-methyl-5-(1-oxoisoindole-2-yl)phenyl)ethylsulfate (0.74 g, 2.3mmol), 20 mL N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.31 g, 2.6 mmol), anhydrous potassium carbonate (0.72g, 5.2 mmol), trifluoroiodoethane (0.54 g, 2.6 mmol) into a 100 mL three-necked flask, and heat the reaction system to 50°C. After reacting for 2 hours, the reaction solution cooled to room temperature. Add 50 mL of ethyl acetate and 50 mL of water for extraction; after the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered, and the filter cake was collected and dried to obtain 0.72 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.5%, corresponding to a yield of 84%.

[0130] Example 19: Preparation of 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0131]

[0132] 2, 2'-(dithiodicarboxylic acid bis(6-fluoro-4-methyl-3,1-phenylene))bis(isoindol-1-one) (1 g, 1.8 mmol), 20 mL N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.18 g, 1.5 mmol), anhydrous potassium carbonate (0.50 g, 3.6 mmol), trifluoroiodoethane (0.84 g, 4.0 mmol) were weighed and added to a 100 mL three-necked flask, and the reaction system was heated to 50°C. After reacting for 2 hours, the reaction solution was cooled to room temperature. 50 mL of ethyl acetate and 50 mL of water were added for extraction; after the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered, the filter cake was collected and dried, and 1.12 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one was obtained, with a HPLC quantitative content of 98.9%, corresponding to a yield of 86%.

[0133] Example 20: Preparation of 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0134]

[0135] Weigh 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one (2.6 g, 8.3 mmol), 50 mL of N, N-dimethylformamide, sodium formaldehyde sulfoxylate (1.1 g, 9.3 mol), anhydrous potassium carbonate (3.4 g, 24.6 mmol), and ethyl 2, 2, 2-trifluoro-p-toluenesulfonate (2.3 g, 9.1 mmol) into a 100 mL three-necked flask, and heat the reaction system to 50°C. After 16 hours of reaction, the reaction solution was cooled to room temperature. The reaction solution was added with 50 mL of ethyl acetate and 50 mL of water for extraction. The organic phase was washed with saturated sodium bicarbonate. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 2.76 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one. The HPLC quantitative content was 98.5%, and the corresponding yield was 94%.

[0136] Example 21: Preparation of 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0137]

[0138] Weigh 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one (3 g, 11 mmol), 50 mL of N, N-dimethylformamide, sodium formaldehyde sulfoxylate (1.4 g, 12.1 mol), anhydrous potassium carbonate (3 g, 22 mmol), and 2, 2, 2-trifluoroethyl benzenesulfonate (2.6 g, 12.1 mmol) into a 100 mL three-necked flask, and heat the reaction system to 50°C. After 12 hours of reaction, cool the reaction solution to room temperature. The reaction solution was added with 50 mL of ethyl acetate and 50 mL of water for extraction. The organic phase was washed with saturated sodium bicarbonate. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 3.74 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one. The HPLC quantitative content was 98.6%, and the corresponding yield was 94.6%.

[0139] Example 22: Preparation of 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0140]

[0141] Weigh 2-(2-fluoro-5-mercapto-4-methylphenyl)isoindol-1-one (3 g, 11 mmol), 50 mL of N, N-dimethylformamide, sodium formaldehyde sulfoxylate (1.4 g, 12.1 mol), anhydrous potassium carbonate (3 g, 22 mmol), and 2, 2, 2-trifluoroethyl methanesulfonate (2.15 g, 12.1 mmol) into a 100 mL three-necked flask, and heat the reaction system to 50°C. After reacting for 20 hours, the reaction solution was cooled to room temperature. The reaction solution was added with 50 mL of ethyl acetate and 50 mL of water for extraction. The organic phase was washed with saturated sodium bicarbonate. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 3.66 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one. The HPLC quantitative content was 98.3%, and the corresponding yield was 92.3%.

[0142] Example 23: Preparation of 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)sulfoxide)phenyl)isoindol-1-one

[0143]

[0144] Weigh 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one (1 g, 2.8 mmol) into a 100 mL three-necked flask, add 30 mL of dichloromethane, place the system in an ice-water bath, control the temperature at 0~5℃, and add m-chloroperbenzoic acid (0.57 g, 2.8 mmol, 85% purity) in batches. After reacting for 3 hours, add 50 mL of dichloromethane to dilute, wash with sodium thiosulfate aqueous solution and saturated sodium bicarbonate solution in sequence, dry and filter the organic phase with anhydrous magnesium sulfate, and concentrate to obtain 0.9 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)sulfoxide)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.6%, corresponding to a yield of 88%.

[0145] Example 24: Preparation of 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)sulfoxide)phenyl)isoindol-1-one

[0146]

[0147] 2-(2-fluoro-4-methyl-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one (1 g, 2.8 mmol), 50 mL of dichloromethane, H2O2 (1.59 g, 30% mass concentration, 14 mmol), acetylacetone (0.28 g, 2.8 mmol), and stannous chloride dihydrate (0.13 g, 0.56 mmol) were weighed and added to a 100 mL reaction bottle and kept at 25°C for 24 hours. 50 mL of dichloromethane was added to dilute, and the mixture was washed with sodium thiosulfate aqueous solution and saturated sodium bicarbonate solution in sequence. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1 g of white solid 2-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.5% and a corresponding yield of 94.2%.

[0148] Example 25: Preparation of 2-(4-chloro-2-fluorophenyl)isoindole-1,3-dione

[0149]

[0150] Add 2-fluoro-4-chloroaniline (10 g, 68.9 mmol), 250 mL toluene and phthalic anhydride (10.6 g, 71.6 mmol) to a 500 mL reaction bottle, reflux and separate water under stirring. After 12 hours of reaction, the reaction solution cools to room temperature. Concentrate the reaction system to dryness, add 200 mL ethyl acetate, extract with 200 mL water, wash with saturated sodium bicarbonate solution and saturated brine in sequence, dry the organic phase with anhydrous magnesium sulfate and concentrate to obtain 18 g of white solid 2-(4-chloro-2-fluorophenyl)isoindole-1, 3-dione, with a HPLC quantitative content of 98.2%, corresponding to a yield of 93%.

[0151] Example 26: Preparation of 2-chloro-5-(1,3-dioxoisoindol-2-yl)-4-fluorobenzenesulfonyl chloride

[0152]

[0153] Chlorosulfonic acid (457.6 g, 3.92 mol) was added into a 1000 mL three-necked flask, and 2-(4-chloro-2-fluorophenyl)isoindole-1, 3-dione (18 g, 65.4 mmol) was added in batches. The system was heated to 70°C and reacted for 3 hours. The reaction solution was slowly dripped into ice water to precipitate a white solid, which was filtered off with suction. The filter cake was dried to obtain 21 g of a white solid 2-chloro-5-(1,3-dioxoisoindol-2-yl)-4-fluorobenzenesulfonyl chloride. The HPLC quantitative content was 98.2%, and the corresponding yield was 89%.

[0154] Example 27: Preparation of 2-chloro-5-(1,3-dioxoisoindol-2-yl)-4-fluorobenzenesulfonyl chloride

[0155]

[0156] Chlorosulfonic acid (4.2 g, 36 mmol) was added to a 50 mL three-necked flask, and 2-(4-chloro-2-fluorophenyl)isoindole-1, 3-dione (1 g, 3.6 mmol) was added in batches, and then the temperature was raised to 120°C. After reacting for 10 minutes, the reaction solution was cooled to room temperature. The reaction solution was slowly dripped into ice water, and a white solid was precipitated and filtered. The filter cake was taken and dried to obtain 1.26 g of white solid 2-chloro-5-(1, 3-dioxoisoindol-2-yl)-4-fluorobenzenesulfonyl chloride, with a HPLC quantitative content of 98.2%, and a corresponding yield of 91.2%.

[0157] Example 28: Preparation of 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindol-1-one

[0158]

[0159] 2-Chloro-5-(1,3-dioxoisoindole-2-yl)-4-fluorobenzenesulfonyl chloride (1 g, 2.7 mmol) and acetic acid (9.6 g, 160.8 mmol) were added to a 100 mL reaction bottle, and zinc powder (1.76 g, 27 mmol) was added under stirring. After reacting at 120 °C for 30 minutes, the reaction solution was filtered while hot. Rinse with 10 mL of ethyl acetate, concentrate the reaction solution to dryness, add 100 mL of ethyl acetate and 100 mL of water to extract, wash with saturated brine, dry the organic phase with anhydrous magnesium sulfate and concentrate to obtain 0.75 g of white solid 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindole-1-one, with a HPLC quantitative content of 98.7%, corresponding to a yield of 96%.

[0160] Example 29: Preparation of 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindol-1-one and S-(2-chloro-4-fluoro-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate

[0161]

[0162]

[0163] Add 2-chloro-5-(1,3-dioxoisoindol-2-yl)-4-fluorobenzenesulfonyl chloride (1 g, 2.7 mmol) and acetic acid (9.6 g, 160.8 mmol) to a 100 mL reaction bottle, add zinc powder (1.76 g, 27 mmol) under stirring, react at 120 °C for 5 hours, and filter the reaction solution while it is hot. The reaction mixture was rinsed with 10 mL of ethyl acetate, concentrated to dryness, extracted with 100 mL of ethyl acetate and 100 mL of water, washed with saturated saline, and the organic phase was dried over anhydrous magnesium sulfate and concentrated. 0.2 g of 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindol-1-one as a white solid was obtained by column chromatography, with a HPLC quantitative content of 98.3% and a corresponding yield of 25%; 0.58 g of S-(2-chloro-4-fluoro-5-(1-oxoisoindol-2-yl)phenyl)ethylsulfate as a white solid, with a HPLC quantitative content of 98.5% and a corresponding yield of 65%. The total yield of 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindol-1-one and S-(2-chloro-4-fluoro-5-(1-oxoisoindol-2-yl)phenyl)ethylsulfate was 90%.

[0164] Example 30: Preparation of S-(2-chloro-4-fluoro-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate

[0165]

[0166] 2-Chloro-5-(1, 3-dioxoisoindole-2-yl)-4-fluorobenzenesulfonyl chloride (1 g, 2.7 mmol) and acetic acid (9.6 g, 160.8 mmol) were added to a 100 mL reaction bottle, and zinc powder (1.76 g, 27 mmol) was added under stirring. After reacting at 120 °C for 36 hours, the reaction solution was filtered while hot. Rinse with 10 mL of ethyl acetate, concentrate the reaction solution to dryness, add 100 mL of ethyl acetate and 100 mL of water to extract, wash with saturated brine, dry the organic phase with anhydrous magnesium sulfate and concentrate, and obtain 0.81 g of white solid S-(2-chloro-4-fluoro-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate, with a HPLC quantitative content of 98.2%, corresponding to a yield of 90%.

[0167] Example 31: Preparation of S-(2-chloro-4-fluoro-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate

[0168]

[0169] Weigh 2-chloro-5-(1, 3-dioxoisoindole-2-yl)-4-fluorobenzenesulfonyl chloride (10 g, 26.8 mmol), acetic acid (21.9 g, 364.6 mmol), acetic anhydride (10.94 g, 107.2 mmol), red phosphorus (4.98 g, 160.8 mmol), and iodine (0.68 g, 2.6 mmol) into a 250 mL reaction bottle, and heat the reaction system to reflux. After 1 hour of reaction, add zinc powder (17.5 g, 267.6 mmol) and acetic acid (96.6 g, 1.6 mol), and continue reflux reaction for 12 hours. The reaction solution was filtered hot, the filter residue was washed with ethyl acetate, the filtrate and the washing solution were combined, concentrated under reduced pressure, the residue was extracted with ethyl acetate and water, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine in sequence, the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 8.2 g of white solid S-(2-chloro-4-fluoro-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate, with a HPLC quantitative content of 99.1%, corresponding to a yield of 90%.

[0170] Example 32: Preparation of 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindol-1-one

[0171]

[0172] Weigh S-(2-chloro-4-fluoro-5-(1-oxoisoindole-2-yl)phenyl)ethylsulfate (1 g, 2.98 mmol), 10 mL tetrahydrofuran, sodium formaldehyde sulfoxylate (0.39 g, 3.28 mmol) and add them to a 50 mL reaction bottle. Cool to 0-5°C and start adding sodium hydroxide solution (0.25 g dissolved in 5 mL water). Keep the temperature at 10°C and continue to heat for 30 minutes after the addition is complete. Add 50 mL water and 50 mL dichloromethane to the reaction solution for extraction. Concentrated hydrochloric acid (0.65 g, 6.6 mmol) was added to the aqueous phase. After the addition was complete, stirring was continued. White solid was continuously precipitated. 50 mL of dichloromethane was added for extraction. The organic phase was dried and concentrated to obtain 0.73 g of white solid 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindol-1-one. The HPLC quantitative content was 98%, and the corresponding yield was 84%.

[0173] Example 33: Preparation of 2,2'-(disulfide diacetylbis(4-chloro-6-fluoro-3,1-phenylene))bis(isoindol-1-one)

[0174]

[0175] Weigh 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindol-1-one (1 g, 3.41 mmol) and 10 mL tetrahydrofuran, add to a 50 mL reaction bottle, cool to 0~5°C, start dripping sodium hydroxide aqueous solution (0.29 g dissolved in 5 mL water), control the reaction temperature not to exceed 10°C, and continue to keep the temperature for 30 minutes after the addition is complete. Add 50 mL of water and 50 mL of dichloromethane to the reaction solution for extraction, dry and concentrate the organic phase to obtain 0.87 g of white solid 2,2'-(dithiodicarbonylbis(4-chloro-6-fluoro-3,1-phenylene))bis(isoindol-1-one), with a HPLC quantitative content of 98.2%, corresponding to a yield of 87%.

[0176] Example 34: Preparation of 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0177]

[0178] 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindol-1-one (1 g, 3.4 mmol), potassium carbonate (0.94 g, 6.8 mmol), 10 mL N,N-dimethylformamide, sodium formaldehyde sulfoxylate (0.44 g, 3.7 mmol), and 2-iodo-1,1,1-trifluoroethane (0.78 g, 3.7 mol) were weighed and added into a 100 mL three-necked flask. After reacting at room temperature for 2 hours, 50 mL ethyl acetate and 50 mL water were added for extraction. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 1.23 g of white solid 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.7% and a corresponding yield of 93%.

[0179] Example 35: Preparation of 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0180]

[0181] Weigh S-(2-chloro-4-fluoro-5-(1-oxoisoindole-2-yl)phenyl)ethylsulfate (1 g, 3.0 mmol), 20 mL of N,N-dimethylformamide, sodium formaldehyde sulfoxylate (0.39 g, 3.3 mmol), trifluoroiodoethane (0.69 g, 3.3mmol), and anhydrous potassium carbonate (0.86 g, 6.2 mmol) into a 100 mL three-necked flask, and heat the reaction system to 50°C. After reacting for 2 hours, the reaction solution cooled to room temperature. Add 50 mL of ethyl acetate and 50 mL of water for extraction. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 1.0 g of white solid 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.6%, corresponding to a yield of 87%.

[0182] Example 36: Preparation of 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0183]

[0184] 2, 2'-(dithiodicarboxylic acid bis(4-chloro-6-fluoro-3,1-phenylene))bis(isoindol-1-one) (1 g, 1.7 mmol), 20 mL N, N-dimethylformamide, sodium formaldehyde sulfoxylate (0.16 g, 1.3 mmol), anhydrous potassium carbonate (0.47 g, 3.4 mmol), trifluoroiodoethane (0.79 g, 3.76 mmol) were weighed and added to a 100 mL three-necked flask, and the reaction system was heated to 50°C. After reacting for 2 hours, the reaction solution was cooled to room temperature. 50 mL of ethyl acetate and 50 mL of water were added for extraction; after the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered, the filter cake was collected and dried, and 1.1 g of white solid 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one was obtained, with a HPLC quantitative content of 98.5%, corresponding to a yield of 84.6%.

[0185] Example 37: Preparation of 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0186]

[0187] Weigh 2-(4-chloro-2-fluoro-5-mercaptophenyl)isoindol-1-one (3 g, 10.2 mmol), N, N50 mL of dimethylformamide, sodium formaldehyde sulfoxylate (1.3 g, 11.5 mol), anhydrous potassium carbonate (3.1 g, 22.5 mmol), and 2,2, 2-trifluoroethyl methanesulfonate (2 g, 11.2 mmol) were added to a 100 mL three-necked flask, and the reaction system was heated to 50°C. After 22 hours of reaction, the reaction solution was cooled to room temperature. 50 mL of ethyl acetate and 50 mL of water were added to the reaction solution for extraction, and the organic phase was washed with saturated sodium bicarbonate. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 3.45 g of white solid 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.5% and a corresponding yield of 88.6%.

[0188] Example 38: Preparation of 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one

[0189]

[0190] Weigh S-(2-chloro-4-fluoro-5-(1-oxoisoindole-2-yl)phenyl)ethyl sulfate (3 g, 8.9 mmol), N, N 50 mL of dimethylformamide, sodium formaldehyde sulfoxylate (1.16 g, 9.8 mol), anhydrous potassium carbonate (3.7 g, 26.8 mmol), and ethyl 2, 2, 2-trifluoro-p-toluenesulfonate (2.5 g, 9.8 mmol) were added to a 100 mL three-necked flask, and the reaction system was heated to 50°C. After 16 hours of reaction, the reaction solution was cooled to room temperature. 50 mL of ethyl acetate and 50 mL of water were added to the reaction solution for extraction, and the organic phase was washed with saturated sodium bicarbonate. After the organic phase was dried and concentrated, a small amount of petroleum ether was added, stirred, and filtered. The filter cake was collected and dried to obtain 3.19 g of white solid 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.6%, and a corresponding yield of 93.6%.

[0191] Example 39: Preparation of 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one

[0192]

[0193] Weigh 2-(4-chloro-2-fluoro-5-((2, 2, 2-trifluoroethyl)thio)phenyl)isoindol-1-one (0.5 g, 1.3 mmol) into a 100 mL three-necked flask, add 20 mL of dichloromethane, place the system in an ice-water bath, control the temperature at 0~5°C, add m-chloroperbenzoic acid (0.23 g, 1.3 mmol, 85% purity) in batches, react for 2 hours, add 20 mL of dichloromethane to dilute, wash with sodium thiosulfate aqueous solution and saturated sodium bicarbonate solution in sequence, dry and filter the organic phase over anhydrous magnesium sulfate, and concentrate to obtain 0.46 g of white solid 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.1% and a corresponding yield of 88%.

[0194] Example 40: Preparation of 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one

[0195]

[0196] 2-(4-chloro-2-fluoro-5-((2,2,2-trifluoroethyl)thio)phenyl)isoindol-1-one (1 g, 2.6 mmol), 50 mL dichloromethane H2O2 (1.5 g, 30%ag, 13 mmol), acetylacetone (0.27 g, 2.6 mmol), stannous chloride dihydrate (0.12 g, 0.53 mmol) were weighed and added to a 100 mL reaction bottle and kept at 25°C for 24 hours. 50 mL dichloromethane was added to dilute, and the mixture was washed with sodium thiosulfate aqueous solution and saturated sodium bicarbonate solution in sequence. The organic phase was dried and filtered with anhydrous magnesium sulfate, and concentrated to obtain 0.96 g of white solid 2-(4-chloro-2-fluoro-5-((2, 2, 2-trifluoroethyl)sulfinyl)phenyl)isoindol-1-one, with a HPLC quantitative content of 98.4% and a corresponding yield of 90.8%.

[0197] The NMR and mass spectrometry data of some compounds and intermediates prepared by the present invention are shown in Table 2:

[0198] Table 2

[0199]

[0200]

[0201]

[0202] .

[0203] According to the preparation method disclosed in the present invention, other compounds of the general formula I (compounds I.1-I.36) described in the following Table 3 and other compounds of the general formula II (compounds II.1-II.36) described in Table 4 can also be prepared.

[0204]

[0205] Formula I

[0206] Table 3

[0207]

[0208]

[0209]

[0210] Formula II

[0211] Table 4

[0212]

[0213]

[0214] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that these are only examples, and various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the protection scope of the present invention is limited by the appended claims.

Claims

1. A method for preparing a trifluoroethyl sulfide substituted benzene compound represented by general formula II, comprising the following steps: Step 1): subjecting the compound of general formula VII to a condensation reaction with the compound of general formula VI to obtain a compound of general formula V; Step 2): subjecting the compound of formula V to a sulfonation reaction to obtain a compound of formula IV; Step 3): The compound of formula IV undergoes a reduction reaction to obtain a compound of formula III; Step 4): The compound of formula III undergoes an alkylation reaction to obtain a compound of formula II; in: R1 and R2 are each independently selected from hydrogen, halogen, cyano, C1-C 10 Alkyl or C1-C 10 Haloalkyl; R3, R4, R5 and R6 are each independently selected from hydrogen, halogen, cyano, nitro, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy or C1-C 10 Haloalkoxy; R7 is selected from hydrogen, acetyl or G; In step 1), the compound of formula VII and the compound of formula VI are dissolved in solvent A and reacted at a temperature between 0°C and the boiling point of solvent A to obtain a compound of formula V; In step 2), the compound of formula V is reacted with a sulfonating agent at a temperature of -10°C to 200°C to obtain a compound of formula IV; In step 3), the compound of formula IV reacts with a reducing agent at a temperature of 0°C to 200°C to obtain a compound of formula III; In step 4), the compound of formula III is reacted with a halogenating agent or a sulfonate and a base in solvent B at a temperature ranging from 0°C to the boiling point of the solvent B to obtain a compound of formula II; the halogenating agent is selected from trifluoroiodoethane; the sulfonate is selected from one or more of 2,2,2-trifluoroethyl methanesulfonate, 2,2,2-trifluoroethyl benzenesulfonate or 2,2,2-trifluoroethyl p-toluenesulfonate; the base is selected from one or more of trimethylamine, triethylamine, pyridine, DBU, N,N-diisopropylmethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide or sodium tert-butoxide.

2. The method according to claim 1, wherein: R1 and R2 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl or C1-C6 haloalkyl; And / or, R3, R4, R5 and R6 are each independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy.

3. The method according to claim 1, wherein: R1 and R2 are each independently selected from hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; And / or, R3, R4, R5 and R6 are each independently selected from hydrogen, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 haloalkoxy.

4. The method according to claim 1, wherein: R1 and R2 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano or methyl; and / or, R3, R4, R5 and R6 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy.

5. The method according to claim 1, wherein: R1 is fluorine, R2 is selected from methyl or chlorine; and / or, R3 and R6 are hydrogen, and R4 and R5 are each independently selected from hydrogen or fluorine.

6. A method for preparing a trifluoroethyl sulfoxide substituted benzene compound represented by general formula I, comprising the following steps: Step 1') preparing a compound of formula II according to the method of claim 1; Step 2') subjecting the compound of formula II to an oxidation reaction to obtain a compound of formula I; in, R1 to R6 are as defined in claim 1; In step 2'), the compound of formula II is reacted with an oxidizing agent in a solvent C at a temperature ranging from -10°C to the boiling point of the solvent C to obtain a compound of formula I.

7. The method according to any one of claims 1 to 6, wherein: R1, R2, R3, R4, R5, R6 and R7 are defined as follows:

8. The method according to any one of claims 1 to 6, wherein: In step 1), the molar ratio of the compound of formula VII to the compound of formula VI is 1:1-3; And / or, in step 2): the compound of formula V is reacted with a sulfonating agent at a temperature of -10°C to 160°C to obtain a compound of formula IV.

9. The method according to claim 8, wherein: The molar ratio of the compound of formula VII to the compound of formula VI is 1:1-2; And / or, the molar ratio of the compound of formula V to the sulfonation reagent is 1:1-100.

10. The method according to claim 8, wherein: The molar ratio of the compound of formula VII to the compound of formula VI is 1:1-1.5; And / or, the molar ratio of the compound of formula V to the sulfonation reagent is 1:1-80.

11. The method according to claim 8, wherein: The molar ratio of the compound of formula VII to the compound of formula VI is 1:1-1.

1.

12. The method according to any one of claims 1 to 6, wherein: The solvent A is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dimethyl ether, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butyl ketone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide; And / or, the sulfonating agent is selected from one or more of chlorosulfonic acid, concentrated sulfuric acid, oleum, sulfur trioxide and sulfur monochloride.

13. The method according to any one of claims 1 to 6, wherein: In step 3), the compound of formula IV is reacted with a reducing agent at a temperature of 0°C to 150°C to obtain a compound of formula III; And / or, in step 4): the molar ratio of the compound of formula III to the halogenating agent or sulfonate and the base is 1:1-5:1-5.

14. The method according to claim 13, wherein: In step 3), the compound of formula IV is reacted with a reducing agent at a temperature of 0°C to 130°C to obtain a compound of formula III; And / or, in step 4): the molar ratio of the compound of formula III to the halogenating agent or sulfonate and the base is 1:1-4:1-4.

15. The method according to claim 13, wherein: In step 3), the compound of formula IV is reacted with a reducing agent at a temperature of 0°C to 120°C to obtain a compound of formula III; And / or, in step 4): the molar ratio of the compound of formula III to the halogenating agent or sulfonate and the base is 1:1-4:1-3.

16. The method according to claim 13, wherein: In step 3), the reducing agent is composed of a transition metal and an acid, the acid is selected from an organic acid or an inorganic acid, and the molar ratio of the compound of formula IV to the transition metal and the acid is 1:1-50:1-100; And / or, in step 4): the molar ratio of the compound of formula III to the halogenating agent or sulfonate and the base is 1:1-3:1-2.

17. The method according to claim 16, wherein: In step 3), the molar ratio of the compound of formula IV to the transition metal and the acid is 1:1-30:1-100.

18. The method according to claim 16, wherein: In step 3), the molar ratio of the compound of formula IV to the transition metal and the acid is 1:1-20:1-80.

19. The method according to claim 16, wherein: In step 3), the molar ratio of the compound of formula IV to the transition metal and the acid is 1:5-15:5-60.

20. The method according to claim 6, wherein: In step 2'), the molar ratio of the compound of formula II to the oxidizing agent is 1:1-10.

21. The method according to claim 6, wherein: In step 2'), the molar ratio of the compound of formula II to the oxidizing agent is 1:1-8.

22. The method according to claim 6, wherein: In step 2'), the molar ratio of the compound of formula II to the oxidizing agent is 1:1-6.

23. The method according to claim 6, wherein: In step 2'), the molar ratio of the compound of formula II to the oxidizing agent is 1:1-5.

24. The method according to claim 16, wherein: The transition metal is selected from zinc, iron, copper or nickel or a mixture of zinc, iron, copper and nickel in any proportion; the acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid and nitric acid.

25. The method according to any one of claims 1 to 6, wherein: The solvent B is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, ethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dimethyl ether, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butyl ketone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, water, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.

26. The method according to claim 6, wherein: The oxidizing agent is selected from one or more of meta-chloroperbenzoic acid, hydrogen peroxide or sodium periodate; And / or, the solvent C is selected from one or more of benzene, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, pentane, hexane, octane, cyclohexane, dichloromethane, chloroform, dioxane, methanol, ethanol, isopropanol, ethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol dimethyl ether, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butyl ketone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, water, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide.

27. The method according to any one of claims 1 to 6, wherein: In the reaction of step 3), red phosphorus and iodine are also added.

28. The method according to claim 27, wherein: The molar ratio of the compound of general formula IV to red phosphorus and iodine is 1:1-10:0.02-0.

2.

29. The method according to claim 27, wherein: The molar ratio of the compound of general formula IV to red phosphorus and iodine is 1:2-8:0.05-0.

15.

30. The method of claim 27, wherein: The molar ratio of the compound of general formula IV to red phosphorus and iodine is 1:2-6:0.05-0.

1.

31. A compound having a structure shown in general formula III: in: R1 to R7 are as defined in any one of claims 1 to 6.

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