Preparation method of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid

Abstract

The invention discloses a preparation method of 2-chloro-3-methyl-4-(methylsulfonyl) benzoic acid, which comprises the following steps: by taking 2, 6-dimethylchlorobenzene as an initial raw material, carrying out Friedel-Crafts acylation reaction, reduction reaction, methylation reaction and oxidation reaction to obtain the 2-chloro-3-methyl-4-(methylsulfonyl) benzoic acid. The starting raw material 2, 6-dimethylchlorobenzene is cheap and easy to obtain; the preparation process does not involve a diazotization reaction, does not use a methyl sulfide reagent, takes oxygen as a green oxidant, and is high in yield of each step, simple and convenient to operate and suitable for industrial mass production.

Description

Technical Field

[0001] The invention relates to the technical field of fine chemical intermediate synthesis, and in particular to a method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid. Background Art

[0002] Tembotrione is a type of benzoylcyclohexanedione herbicide launched by Bayer in 2007 based on the inhibition of p-hydroxyphenylpyruvate dioxygenase activity. It can effectively kill many annual grass weeds and broadleaf weeds.

[0003] At present, the production process of tampoxone is mainly based on the process developed by Bayer (DE 19846792A1), which uses 2-methyl-3-chloroaniline 1 as the starting material, obtains the acyl chloride intermediate 9 through 10 steps of reaction, and then condenses with 1,3-cyclohexanedione and rearranges to obtain tampoxone.

[0004]

[0005] In the above route, compound No. 5, 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, is an important intermediate of the herbicide cyclosulfone. The preparation method mentioned in DE 19846792A1 requires a diazotization reaction and the use of a methyl sulfide reagent with an unpleasant odor. Although Chinese patent document CN 117126084 A (application number 202311003736.X) has made some improvements to the preparation method of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, it uses 3-chloro-2-methylbenzyl sulfide as the starting material, and the preparation of 3-chloro-2-methylbenzyl sulfide still requires a diazotization reaction and the use of a methyl sulfide reagent with an unpleasant odor.

[0006] Regarding the preparation method of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, in addition to the preparation method disclosed in DE 19846792A1, Chinese patent document CN 118619857 A (application number 202310222395.9) discloses a preparation method of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, wherein 2-chloro-3-methyl-4-methylsulfonylacetophenone is dissolved in an organic solvent, and then chlorine gas is introduced to carry out a chlorination reaction, and then a hydrolysis reaction is carried out, and acidification is carried out to obtain 2-chloro-3-methyl-4-methylsulfonylbenzoic acid. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a preparation method of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid which is suitable for industrial production, has low cost and is more environmentally friendly.

[0008] The technical solution for achieving the purpose of the present invention is a method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, comprising the following steps:

[0009] ①2,6-Dimethylchlorobenzene undergoes Friedel-Crafts acylation to generate 2,4-dimethyl-3-chloro-benzenesulfonyl chloride.

[0010] ②2,4-dimethyl-3-chloro-benzenesulfonyl chloride is reduced to generate 2,4-dimethyl-3-chloro-benzenesulfinic acid.

[0011] ③2,4-Dimethyl-3-chloro-benzenesulfinic acid reacts with a methylating agent to generate 2,6-dimethyl-3-methylsulfonylchlorobenzene.

[0012] ④2,6-Dimethyl-3-methylsulfonyl chlorobenzene is oxidized in the presence of oxygen and a catalyst to produce 2-chloro-3-methyl-4-methylsulfonylbenzoic acid.

[0013] Optionally, in step ①, 2,6-dimethylchlorobenzene reacts with excess chlorosulfonic acid to directly obtain 2,4-dimethyl-3-chloro-benzenesulfonyl chloride, the molar ratio of 2,6-dimethylchlorobenzene to chlorosulfonic acid is 1:1-6, preferably 1:2-6, and the reaction temperature is 20°C-25°C.

[0014] Alternatively, 2,6-dimethylchlorobenzene is first reacted with chlorosulfonic acid and then with thionyl chloride to obtain 2,4-dimethyl-3-chloro-benzenesulfonyl chloride. 2,6-dimethylchlorobenzene is reacted with chlorosulfonic acid at 20°C-25°C for 5h-18h, the solvent is removed, and then thionyl chloride is added to react at 50-60°C with stirring; the molar ratio of 2,6-dimethylchlorobenzene to chlorosulfonic acid is 1:1-2, and the molar ratio of thionyl chloride to 2,6-dimethylchlorobenzene is 3-12:1.

[0015] In step ②, 2,4-dimethyl-3-chloro-benzenesulfonyl chloride is reduced to 2,4-dimethyl-3-chloro-benzenesulfinic acid or 2,4-dimethyl-3-chloro-benzenesulfinic acid salt under alkaline conditions.

[0016] The reducing agent used is one of sodium sulfite, potassium sulfite, sulfurous acid, zinc powder, sodium sulfide, potassium sulfide, sodium bisulfite or a combination of more than one of them.

[0017] The base used is one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate, or a combination of more than one of them.

[0018] In the above step ②, the reduction reaction can be carried out in a nitrogen atmosphere, the molar ratio of 2,4-dimethyl-3-chloro-benzenesulfonyl chloride to the reducing agent is 1:1-10, the reduction reaction temperature is 20-150° C., and the reaction is stirred until the raw material disappears.

[0019] In the above step ③, the methylating agent is one or a combination of dimethyl sulfate, methyl iodide, methyl bromide, methyl chloride, dimethyl carbonate, methyl trifluoromethanesulfonate, methyl methanesulfonate, diazomethane, chloro / bromoacetic acid, and chloro / bromoacetic acid ester derivatives.

[0020] In the above step ③, the chloro / bromoacetic acid ester derivative is methyl chloro / bromoacetate, ethyl chloro / bromoacetate, propyl chloro / bromoacetate, isopropyl chloro / bromoacetate, tert-butyl chloro / bromoacetate or benzyl chloro / bromoacetate.

[0021] In the above step ③, the methylation reaction can be carried out under the protection of nitrogen atmosphere, and the reaction temperature is 20-150° C.; the molar ratio of 2,4-dimethyl 3-chlorobenzenesulfinic acid to the methylation agent is 1:1-6.

[0022] In the above step ④, the catalyst is a persulfate compound, a cobalt compound, a combination of a cobalt compound and a bromine compound, a combination of a cobalt compound / manganese compound and a bromide, a combination of a nickel compound / manganese compound and a bromine compound, or a combination of a cobalt compound and N-hydroxyimide.

[0023] Optionally, when the catalyst is a combination of a cobalt compound and a bromine compound, the molar ratio of Co / Br is 1:0.5-1.5; when the catalyst is a combination of a cobalt compound, a manganese compound and a bromine compound, the molar ratio of Co / Mn / Br is 1:1-5:0.1-1; when the catalyst is a combination of a nickel compound, a manganese compound and a bromine compound, the molar ratio of Ni / Mn / Br is 1:1-5:0.1-1.

[0024] The cobalt compound is one or a combination of cobalt acetate, cobalt bromide, cobalt chloride, cobalt acetylacetonate, cobalt nitrate, cobalt carbonate, cobalt oxide and crystalline hydrates of the above cobalt compounds.

[0025] The manganese compound is one or a combination of manganese acetate, manganese bromide, manganese chloride, manganese carbonate and crystalline hydrates of the above manganese compounds.

[0026] The nickel compound is one or a combination of nickel chloride, nickel bromide, nickel acetylacetonate, nickel acetate, nickel sulfate, nickel nitrate or hydrates of the above nickel compounds.

[0027] The bromine compound is one or a combination of more than one of bromine, organic bromide or inorganic bromine compounds.

[0028] The organic bromide is an alkyl bromide or an aryl bromide; the inorganic bromide is one or a combination of hydrogen bromide, metal bromide, ammonium bromide, quaternary ammonium bromide salt, and an ionic liquid whose anion is bromide;

[0029] The N-hydroxyimide is one or a combination of N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxytetrachlorophthalimide, and N,N,N-trihydroxyisocyanuric acid.

[0030] In step ④, the amount of the catalyst used is 0.1%-40% of the amount of the reaction raw material 2,6-dimethyl-3-methylsulfonylchlorobenzene, and the oxygen pressure is 1 atmosphere to 10 atmospheres.

[0031] Furthermore, in step ④, the oxidation reaction temperature is 50-150°C.

[0032] The present invention has positive effects:

[0033] The invention uses 2,6-dimethylchlorobenzene as a starting material, and obtains 2-chloro-3-methyl-4-methylsulfonylbenzoic acid through Friedel-Crafts acylation reaction, reduction reaction, methylation reaction and oxidation reaction; the starting material 2,6-dimethylchlorobenzene is cheap and easily available; the preparation process does not involve diazotization reaction, does not use methyl sulfide reagent, uses oxygen as a green oxidant, has high yield in each step, is simple to operate, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in step ② of Example 1.

[0035] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in step ③ of Example 1.

[0036] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in step ④ of Example 1. DETAILED DESCRIPTION

[0037] Introduced below are some of the multiple possible embodiments of the present invention, which are intended to provide a basic understanding of the present invention, and are not intended to confirm the key or decisive elements of the present invention or to limit the scope of protection. It is easy to understand that according to the technical solution of the present invention, without changing the essential spirit of the present invention, a person of ordinary skill in the art can propose other mutually replaceable implementations. Therefore, the following specific embodiments are only exemplary descriptions of the technical solution of the present invention, and should not be regarded as the whole of the present invention or as a limitation or restriction to the technical solution of the present invention.

[0038] (Example 1)

[0039] The preparation method of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid of the present embodiment comprises the following steps:

[0040] ① Preparation of 2,4-dimethyl-3-chloro-benzenesulfonyl chloride.

[0041]

[0042] Add 2,6-dimethylchlorobenzene (14g, 0.10mol, 1.0eq) to a 1L three-necked flask, add dichloromethane (180g, 10V) to dissolve it. Replace with nitrogen for 5-15 minutes, slowly add chlorosulfonic acid (13g, 0.11mol, 1.1eq) to the reaction system, and add for 1-3h; after the addition is completed, continue to react at 20℃-25℃ for 16h. Concentrate to remove dichloromethane; add thionyl chloride (119g, 1.0mol, 2.5eq), heat the reaction mixture to 50-60℃, react for 6-8h under stirring, and concentrate to a constant weight of about 25g of crude product at the end of the reaction, with HPLC purity >95%.

[0043] ② Preparation of 2,4-dimethyl-3-chloro-benzenesulfinic acid.

[0044]

[0045] Add 2,4-dimethyl 3-chloro-benzenesulfonyl chloride (24 g, 0.10 mol, 1.0 eq) to a 2L three-necked flask, add saturated sodium sulfite aqueous solution (150 g, 25%, 7V), start stirring and control the internal temperature to less than 30°C, slowly add saturated sodium bicarbonate aqueous solution to adjust the pH of the reaction solution to 7-8. After the internal reaction solution pH reaches 7-8, stir at 20-30°C for 16-24 hours under nitrogen protection.

[0046] The reducing agent used in this step is one or a combination of sodium sulfite, potassium sulfite, sulfurous acid, zinc powder, sodium sulfide, potassium sulfide, and sodium bisulfite, preferably sodium sulfite, zinc powder, and sodium sulfite. In this embodiment, it is sodium sulfite.

[0047] The base used in this step is one or a combination of more than one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate, and in this embodiment, it is sodium bicarbonate.

[0048] After cooling to an internal temperature of 0-5°C, the pH was adjusted to 2-4 using concentrated hydrochloric acid (30% aqueous solution). After the pH reached 2-4, the mixture was stirred for 3-5 hours, and the solid was collected by filtration. The solid was washed with water (100 g * 2, i.e., washed twice, 100 g of water each time), filtered, and vacuum dried to obtain 12 g (purity 96%, yield 58%) of 2,4-dimethyl-3-chloro-benzenesulfinic acid. The H NMR spectrum of the product is shown in Figure 1 .

[0049] ③ Preparation of 2,6-dimethyl-3-methylsulfonylchlorobenzene.

[0050]

[0051] Add 2,4-dimethyl 3-chlorobenzenesulfinic acid (12g, 0.058mol, 1.0eq) to a 1L three-necked flask, add DMF (500g, 5V), start stirring to dissolve it; under nitrogen protection, slowly add potassium carbonate (12g, 0.870mol, 1.45eq) in batches. After potassium carbonate is added, continue stirring for 30-60 minutes under nitrogen protection, heat to an internal temperature of 40-50°C, add iodomethane (42.6g, 0.30mol, 1.45eq) at one time, and stir at 40-50°C for 16-24 hours under nitrogen protection. After cooling to an internal temperature of 0-5°C, add 200g of water dropwise, stir for 3-5 hours, filter and collect the solid, wash the solid with water (50g*2), filter, and vacuum dry the solid to obtain 7g of product (purity 95%, yield, 55%). The nuclear magnetic resonance H spectrum of the product is shown in Figure 2 .

[0052] The methylating agent used is one or more of dimethyl sulfate, methyl iodide, methyl bromide, methyl chloride, dimethyl carbonate, methyl trifluoromethanesulfonate, methyl methanesulfonate, diazomethane, chloro / bromoacetic acid, chloro / bromoacetic acid ester derivatives (such as methyl chloro / bromoacetate, ethyl chloro / bromoacetate, propyl chloro / bromoacetate, isopropyl chloro / bromoacetate, tert-butyl chloro / bromoacetate, benzyl chloro / bromoacetate, etc.); preferably dimethyl sulfate, methyl iodide, chloroacetic acid, bromoacetic acid, methyl chloroacetate, ethyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, more preferably dimethyl sulfate, methyl iodide, chloroacetic acid.

[0053] The reduction product sulfinic acid (salt) of step ② can be directly reacted with the methylating agent to obtain methyl sulfone without separation.

[0054] ④ Preparation of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid.

[0055]

[0056] 2,6-Dimethyl-3-methylsulfonylchlorobenzene (11 g, 50 mmol, 1.0 eq) was added to a 100 mL three-necked flask, followed by the addition of hydrated cobalt acetate (2.4 g, 20 mmol, 0.4 eq), butanone (0.11 g, 1.5 mmol, 0.3 eq) and solvent acetic acid (200 mL), and the mixture was replaced with oxygen for 5-15 minutes. After the oxygen replacement was completed, the mixture was heated to an internal temperature of 110-115°C, and the reaction was stirred under 2 atm of oxygen for 24-48 hours.

[0057] The catalyst in this step is a persulfate compound (such as a combination of one or more of potassium persulfate, sodium persulfate, and ammonium persulfate), a cobalt compound, a combination of a cobalt compound and a bromine compound (Co / Br), a combination of a cobalt compound / manganese compound and a bromide (Co / Mn / Br), a combination of a nickel compound / manganese compound and a bromine compound (Ni / Mn / Br), or a combination of a cobalt compound and N-hydroxyimide.

[0058] When the catalyst is a combination of a cobalt compound and a bromine compound, the molar ratio of Co / Br is 1:(0.5-1.5), preferably 1:1; when the catalyst is a combination of a cobalt compound, a manganese compound and a bromine compound, the molar ratio of Co / Mn / Br is 1:(1-5):(0.1-1); when the catalyst is a combination of a nickel compound, a manganese compound and a bromine compound, the molar ratio of Ni / Mn / Br is 1:(1-5):(0.1-1).

[0059] The cobalt compound is cobalt acetate (Co(OAc)2), cobalt bromide (CoBr2), cobalt chloride (COCl2), cobalt acetylacetonate (Co(acac)2), cobalt nitrate (Co(NO3)2), cobalt carbonate (COCO3), cobalt oxide (CoO), and one or more combinations of crystalline hydrates of the above cobalt compounds.

[0060] The manganese compound is one or a combination of manganese acetate (Mn(OAc)2), manganese bromide (MnBr2), manganese chloride (MnCl2), manganese carbonate (MnCO3) and crystalline hydrates of the above manganese compounds.

[0061] The nickel compound may be one or a combination of nickel chloride, nickel bromide, nickel acetylacetonate, nickel acetate, nickel sulfate, nickel nitrate and hydrates of the above nickel compounds.

[0062] The bromine compound can be bromine, an organic bromide or an inorganic bromine compound, or a combination of more than one of them.

[0063] The organic bromide may be an alkyl bromide compound (such as one or a combination of bromoacetic acid, dibromoacetic acid, bromoform, 1,2-dibromoethane) or an aryl bromide (such as one or a combination of benzyl bromide, bromobenzene, dibromobenzene).

[0064] The inorganic bromine compound can be one or a combination of more than one of hydrogen bromide, metal bromide, ammonium bromide, quaternary ammonium bromide salts (such as tetra-n-butylammonium bromide, benzyltriethylammonium bromide, tetramethylammonium bromide, trimethyl-n-butylammonium bromide, etc.), and ionic liquids whose anions are bromine (such as 1-benzyl-3-methylimidazolium bromide, benzyltributylphosphonium bromide, etc.).

[0065] The N-hydroxyimide is one or a combination of N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxytetrachlorophthalimide, and N,N,N-trihydroxyisocyanuric acid.

[0066] The oxygen pressure is 1 atmosphere to 10 atmospheres, preferably 1 atmosphere to 5 atmospheres, more preferably 1 atmosphere to 4 atmospheres.

[0067] After the reaction is completed, the reaction mixture is cooled, concentrated to remove acetic acid, 100 g of water is added, potassium carbonate (7 g, 50 mmol, 1.0 eq) is added in batches, extracted with ethyl acetate (50 mL*3), the aqueous phase is cooled to 0-5°C, the pH is adjusted to 1-2 with 30% concentrated hydrochloric acid, stirred at 0-5°C for 1-2 hours, filtered, and the solid is collected; the collected solid is washed with pure water (30 mL*2), filtered, and the solid is dried to obtain 9.6 g of the product (purity 95%, yield 77.8%). The H NMR spectrum of the product is shown in Figure 3 .

[0068] (Example 2)

[0069] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0070] Step ②: When preparing 2,4-dimethyl-3-chloro-benzenesulfinic acid, 2,4-dimethyl-3-chloro-benzenesulfonyl chloride (0.10 mol, 1.0 eq) was slowly added to a 2L three-necked flask containing sodium sulfite (0.10 mol, 1.0 eq), NaHCO3 (0.3 mol, 3.0 eq) and H2O (40 mL), and stirring was started and the temperature was raised to 70°C, and stirred at this temperature for 1 hour.

[0071] Step ③ Add chloroacetic acid (0.15 mol, 1.5 eq) and 50% (w / w) NaOH aqueous solution (0.15 mol, 1.5 eq). After the addition is complete, continue to heat to 105° C. and stir at this temperature for 20 hours.

[0072] (Example 3)

[0073] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0074] Step ③: When preparing 2,6-dimethyl-3-methylsulfonylchlorobenzene, add 2,4-dimethyl-3-chlorobenzenesulfinic acid (12 g, 0.058 mol, 1.0 eq) to a 1L three-necked flask, add DMF (500 g, 5V), start stirring to dissolve it, and slowly add potassium carbonate (12 g, 0.870 mol, 1.45 eq) in batches under nitrogen protection. After potassium carbonate is added, stir for 30-60 minutes under nitrogen protection, heat to an internal temperature of 40-50°C, add 0.07 mol of dimethyl sulfate (8.8 g, 1.2 eq) at one time, and stir at 40-50°C for 16-24 hours under nitrogen protection. After cooling to an internal temperature of 0-5°C, water (200 g) was added dropwise, stirred for 3-5 hours, and the solid was collected by filtration. The solid was washed with water (50 g*2), filtered, and the solid was vacuum dried to obtain 11.8 g of the product (purity 95%, yield 92%).

[0075] (Example 4)

[0076] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0077] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonylchlorobenzene (1.1 g, 5.0 mmol, 1.0 eq) to a 100 mL three-necked flask, and add cobalt (II) acetylacetonate (0.13 g, 0.5 mmol, 0.1 eq), N-hydroxysuccinimide (0.06 g, 0.5 mmol, 0.1 eq) and solvent acetic acid (20 mL) in sequence, and replace with oxygen for 5-15 minutes. After the oxygen replacement is completed, heat to an internal temperature of 110-115° C., and stir the reaction under 2 atm of oxygen for 24-48 hours. After post-treatment, 0.85 g of the product (purity 95%, yield 68%) is obtained.

[0078] (Example 5)

[0079] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0080] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonylchlorobenzene (1.1 g, 5.0 mmol, 1.0 eq) into a 100 mL three-necked flask, and add cobalt (II) acetylacetonate (0.13 g, 0.5 mmol, 0.1 eq), N-hydroxyphthalimide (0.08 g, 0.5 mmol, 0.1 eq) and solvent acetic acid (20 mL) in sequence, and replace with oxygen for 5-15 minutes; after the oxygen replacement is completed, heat to an internal temperature of 100-120° C., and stir and react for 24-48 hours under 2 atm of oxygen. After post-treatment, 1.15 g of the product (purity 95%, yield 92%) is obtained.

[0081] (Example 6)

[0082] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonyl-chlorobenzene (1.1 g, 5.0 mmol, 1.0 eq) to a 100 mL three-necked flask, and add cobalt (III) acetylacetonate (0.18 g, 0.5 mmol, 0.1 eq), N,N,N-trihydroxyisocyanuric acid (0.088 g, 0.5 mmol, 0.1 eq) and solvent acetic acid (20 mL) in sequence, and replace with oxygen for 5-15 minutes; after the oxygen replacement is completed, heat to an internal temperature of 110-115 ° C, and stir and react under 1 atm of oxygen for 24-48 hours. After post-treatment, 0.7 g of the product is obtained, with a purity of 95% and a yield of 58%.

[0083] (Example 7)

[0084] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0085] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonylchlorobenzene (1.1 g, 5.0 mmol, 1.0 eq) to a 100 mL three-necked flask, and then add ammonium persulfate (2.5 g, 11 mmol, 2.2 eq), pyridine (0.16 g, 0.2 mmol, 0.4 eq) and solvent acetonitrile (11 mL). Oxygen substitution is performed for 5-15 minutes; after oxygen substitution is completed, heat to an internal temperature of 80-90°C and stir for 24-48 hours under 1 atm of oxygen.

[0086] The reaction mixture was cooled, concentrated to remove acetonitrile, water (100 g) was added, potassium carbonate (7 g, 50 mmol, 1.0 eq) was added in batches, extracted with ethyl acetate (20 mL*3), the aqueous phase was cooled to 0-5°C, the pH was adjusted to 1-2 with 30% concentrated hydrochloric acid, stirred at 0-5°C for 1 hour, filtered, the collected solid was washed with pure water (10 mL*2), and the solid was dried to obtain 1.1 g of the product with a purity of 95%.

[0087] (Example 8)

[0088] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0089] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonyl-chlorobenzene (1.1 g, 5.0 mmol, 1.0 eq) to a 100 mL three-necked flask, and then add potassium persulfate (3.0 g, 11 mmol, 2.2 eq), pyridine (0.16 g, 0.2 mmol, 0.4 eq) and solvent acetonitrile (11 mL). Oxygen substitution for 5-15 minutes; after oxygen substitution, heat to an internal temperature of 80-90°C, and stir for 24-48 hours under 2 atm of oxygen. Post-treatment (same method as above) to obtain 1.06 g of product with a purity of 95%.

[0090] (Example 9)

[0091] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0092] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonyl-chlorobenzene (2.2 g, 10.0 mmol, 1.0 eq) into a 100 mL three-necked flask, and add hydrated cobalt acetate (240 mg, 0.2 eq), 48 wt.% HBr aqueous solution (0.45 mL, 0.4 eq) and solvent acetic acid (30 mL) in sequence. Oxygen substitution for 5-15 minutes; after oxygen substitution, heat to an internal temperature of 150°C, and stir for 12-24 hours under 2 atm of oxygen. Post-treatment (same method as before) to obtain 1.86 g of product with a purity of 95%.

[0093] (Example 10)

[0094] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0095] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonyl-chlorobenzene (2.2 g, 10.0 mmol, 1.0 eq) to a 100 mL three-necked flask, and add hydrated cobalt acetate (240 mg, 0.2 eq), hydrated manganese acetate (1.61 g, 0.6 eq), sodium bromide (206 mg, 0.2 eq) and solvent acetic acid (50 mL) in sequence. Oxygen substitution for 5-15 minutes; after oxygen substitution, heat to an internal temperature of 120°C, and stir for 15 hours under 3 atm of oxygen. Post-treatment (same method as before) to obtain 1.56 g of product with a purity of 95%.

[0096] (Example 11)

[0097] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0098] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonyl-chlorobenzene (2.2 g, 10.0 mmol, 1.0 eq) to a 100 mL three-necked flask, and add hydrated cobalt acetate (240 mg, 0.2 eq), hydrated manganese acetate (1.61 g, 0.6 eq), triethylbenzylammonium bromide (707 mg, 0.26 eq) and solvent acetic acid (50 mL) in sequence. Oxygen substitution for 5-15 minutes; after oxygen substitution, heat to an internal temperature of 130°C, and stir for 20 hours under 3 atm of oxygen. Post-treatment (same method as before) to obtain 1.36 g of product with a purity of 95%.

[0099] (Example 12)

[0100] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0101] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonyl-chlorobenzene (2.2 g, 10.0 mmol, 1.0 eq) to a 100 mL three-necked flask, and then add hydrated cobalt acetate (240 mg, 0.2 eq), hydrated manganese acetate (1.61 g, 0.6 eq), 1-benzyl-3-methylimidazolium bromide (1.01 g, 0.4 eq) and solvent acetic acid (50 mL). Oxygen substitution for 5-15 minutes; after oxygen substitution, heat to an internal temperature of 150°C, and stir for 20 hours under 4 atm of oxygen. Post-treatment (same method as before) to obtain 1.28 g of product with a purity of 95%.

[0102] (Example 13)

[0103] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0104] Step ④: When preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, add 2,6-dimethyl-3-methylsulfonyl-chlorobenzene (2.2 g, 10.0 mmol, 1.0 eq) to a 100 mL three-necked flask, and then add nickel chloride (260 mg, 0.2 eq), hydrated manganese acetate (1.61 g, 0.6 eq), sodium bromide (309 mg, 0.3 eq) and solvent acetic acid (80 mL). Oxygen substitution for 5-15 minutes; after oxygen substitution, heat to an internal temperature of 140°C, and stir for 24 hours under 2 atm of oxygen. Post-treatment (same method as above) to obtain 1.86 g of product with a purity of 95%.

[0105] (Example 14)

[0106] The preparation method of this embodiment is the same as that of embodiment 1 except that:

[0107] In step ①, 2,6-dimethylchlorobenzene reacts with chlorosulfonic acid to directly obtain 2,4-dimethyl-3-chloro-benzenesulfonyl chloride.

[0108] 2,6-Dimethylchlorobenzene (14g, 0.10mol, 1.0eq) was added to a 1L three-necked flask, and dichloromethane (180g, 10V) was added to dissolve it. Nitrogen was replaced for 5-15 minutes, and chlorosulfonic acid (51g, 0.44mol) was slowly added to the reaction system, and the addition time was 1-3h; after the addition was completed, the reaction was carried out at 20℃-25℃ for 20h, and after the reaction was completed, the solvent was removed to obtain 23g of 2,4-dimethyl-3-chloro-benzenesulfonyl chloride, with HPLC purity>95%.

[0109] 2,6-dimethylchlorobenzene and chlorosulfonic acid can directly complete the acylation reaction, but when the amount of chlorosulfonic acid is low, for example, when the molar ratio of 2,6-dimethylchlorobenzene to chlorosulfonic acid is 1:1-1.5, the reaction can be carried out, but the yield of the reaction is not as high as when the amount of chlorosulfonic acid is high. Considering the cost problem when the amount of chlorosulfonic acid is high, as described in Example 1, 2,6-dimethylchlorobenzene can be first reacted with a low amount of chlorosulfonic acid, and then reacted with thionyl chloride to obtain 2,4-dimethyl-3-chloro-benzenesulfonyl chloride; in this way, the yield is guaranteed while reducing the amount of chlorosulfonic acid.

Claims

1. A method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, characterized in that The following steps are involved: ①2,6-Dimethylchlorobenzene undergoes Friedel-Crafts acylation to generate 2,4-dimethyl-3-chloro-benzenesulfonyl chloride; ②2,4-dimethyl-3-chloro-benzenesulfonyl chloride is reduced to generate 2,4-dimethyl-3-chloro-benzenesulfinic acid; ③2,4-dimethyl-3-chloro-benzenesulfinic acid reacts with a methylating agent to generate 2,6-dimethyl-3-methylsulfonylchlorobenzene; ④2,6-Dimethyl-3-methylsulfonylchlorobenzene is oxidized in the presence of oxygen and a catalyst to produce 2-chloro-3-methyl-4-methylsulfonylbenzoic acid.

2. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 1, wherein: In step ①, 2,6-dimethylchlorobenzene reacts with chlorosulfonic acid to obtain 2,4-dimethyl-3-chloro-benzenesulfonyl chloride, the molar ratio of 2,6-dimethylchlorobenzene to chlorosulfonic acid is 1:1-6, and the reaction temperature is 20°C-25°C.

3. The preparation method of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 2, characterized in that: In step ①, 2,6-dimethylchlorobenzene is first reacted with chlorosulfonic acid and then with thionyl chloride to obtain 2,4-dimethyl-3-chloro-benzenesulfonyl chloride; 2,6-dimethylchlorobenzene and chlorosulfonic acid react at 20-25°C for 5-18 hours, then remove the solvent, add thionyl chloride, and react at 50-60°C with stirring; The molar ratio of 2,6-dimethylchlorobenzene to chlorosulfonic acid is 1:1-2, and the molar ratio of thionyl chloride to 2,6-dimethylchlorobenzene is 3-12:

1.

4. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 1, wherein: In step ②, 2,4-dimethyl-3-chloro-benzenesulfonyl chloride is reduced to 2,4-dimethyl-3-chloro-benzenesulfinic acid or 2,4-dimethyl-3-chloro-benzenesulfinic acid salt under alkaline conditions; The reducing agent used is one or a combination of more than one of sodium sulfite, potassium sulfite, sulfurous acid, zinc powder, sodium sulfide, potassium sulfide, and sodium bisulfite; The base used is one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate, or a combination of more than one of them.

5. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 4, wherein: In step ②, the molar ratio of 2,4-dimethyl-3-chloro-benzenesulfonyl chloride to the reducing agent is 1:1-10, and the reduction reaction temperature is 20-150°C.

6. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 1, wherein: In step ③, the methylating agent is one or a combination of dimethyl sulfate, methyl iodide, methyl bromide, methyl chloride, dimethyl carbonate, methyl trifluoromethanesulfonate, methyl methanesulfonate, diazomethane, chloro / bromoacetic acid, and chloro / bromoacetic acid ester derivatives.

7. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 6, wherein: In step ③, the chloro / bromoacetic acid ester derivative is methyl chloro / bromoacetate, ethyl chloro / bromoacetate, propyl chloro / bromoacetate, isopropyl chloro / bromoacetate, tert-butyl chloro / bromoacetate or benzyl chloro / bromoacetate.

8. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 6, wherein: In step ③, the methylation reaction temperature is 20-150° C.; the molar ratio of 2,4-dimethyl 3-chlorobenzenesulfinic acid to the methylation agent is 1:1-6.

9. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 1, wherein: In step ④, the catalyst is a persulfate compound, a cobalt compound, a combination of a cobalt compound and a bromine compound, a combination of a cobalt compound / manganese compound and a bromide, a combination of a nickel compound / manganese compound and a bromine compound, or a combination of a cobalt compound and N-hydroxyimide.

10. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 9, characterized in that: When the catalyst is a combination of a cobalt compound and a bromine compound, the molar ratio of Co / Br is 1:0.5-1.5; when the catalyst is a combination of a cobalt compound, a manganese compound and a bromine compound, the molar ratio of Co / Mn / Br is 1:1-5:0.1-1; when the catalyst is a combination of a nickel compound, a manganese compound and a bromine compound, the molar ratio of Ni / Mn / Br is 1:1-5:0.1-1.

11. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 9, characterized in that: The cobalt compound is one or a combination of cobalt acetate, cobalt bromide, cobalt chloride, cobalt acetylacetonate, cobalt nitrate, cobalt carbonate, cobalt oxide, and crystalline hydrates of the above cobalt compounds; The manganese compound is one or a combination of more than one of manganese acetate, manganese bromide, manganese chloride, manganese carbonate and crystalline hydrates of the above manganese compounds; The nickel compound is one or a combination of nickel chloride, nickel bromide, nickel acetylacetonate, nickel acetate, nickel sulfate, nickel nitrate or hydrates of the above nickel compounds; The bromine compound is one or a combination of bromine, organic bromide or inorganic bromine compound; The organic bromide is an alkyl bromide or an aryl bromide; the inorganic bromide is one or a combination of hydrogen bromide, metal bromide, ammonium bromide, quaternary ammonium bromide salt, and an ionic liquid whose anion is bromide; The N-hydroxyimide is one or a combination of N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxytetrachlorophthalimide, and N,N,N-trihydroxyisocyanuric acid.

12. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 1, characterized in that: In step ④, the amount of the catalyst used is 0.1%-40% of the amount of the reaction raw materials, and the oxygen pressure is 1 atmosphere to 10 atmospheres.

13. The method for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoic acid according to claim 1, characterized in that: The oxidation reaction temperature is 50-150°C.

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