A method for preparing methyl 2,3-dimethyl-4-methanesulfonylbenzoate

Abstract

This invention relates to the field of organic synthesis technology, and more particularly to a method for preparing methyl 2,3-dimethyl-4-methanesulfonylbenzoate. The preparation method provided by this invention uses 3-amino-o-xylene as a starting material, and synthesizes the product through reaction steps including diazotization of the methylthio group, bromination, Grignard carboxylation, esterification, and oxidation. The preparation method described in this invention is simple to operate, the reaction process is easy to control, and it avoids the use of flammable and explosive materials such as n-butyllithium and aluminum chloride. The yield of each reaction step can reach over 95%, the intermediate product selectivity is high, the product purity reaches 97.9%, and the overall yield reaches 87.05%.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing methyl 2,3-dimethyl-4-methanesulfonylbenzoate. Background Technology

[0002] 2,3-Dimethyl-4-methanesulfonylbenzoic acid is a key intermediate for benzoxazine. US Patent 614703A1 reports the synthesis of benzoxazine using methyl 2,3-dimethyl-4-methanesulfonylbenzoate as a starting material. A drawback of this synthetic route is the difficulty in obtaining this intermediate on the market. However, the development of a method for synthesizing methyl 2,3-dimethyl-4-methanesulfonylbenzoate has overcome this deficiency. Patent WO2001000584A3 discloses the synthesis of 2,3-dimethyl-4-methanesulfonylbenzoic acid using 2,3-dimethylbenzyl sulfide as a starting material. This synthetic route has a bromination yield of 69%, a Grignard reaction yield of 87%, and an oxidation yield of 88%. The biggest drawback of this synthetic route is the bromination reaction, which uses acetic acid as a solvent, introduces a large amount of sodium acetate in the post-treatment process, increases wastewater volume, and has low product selectivity. Summary of the Invention

[0003] The purpose of this invention is to provide a method for preparing methyl 2,3-dimethyl-4-methanesulfonylbenzoate, which is simple, easy to control, has a high yield, and high selectivity.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0005] This invention provides a method for preparing methyl 2,3-dimethyl-4-methanesulfonylbenzoate, comprising the following steps:

[0006] Copper powder, dimethyl disulfide and 3-amino-o-xylene were mixed, and nitrite was added to carry out a diazotization reaction to obtain 2,3-dimethyl-4-methylthiobenzene;

[0007] Dichloromethane and the 2,3-dimethyl-4-methylthiobenzene were mixed, and liquid bromine was added to carry out a bromination reaction to obtain 2,3-dimethyl-4-methylthiobromobenzene;

[0008] Magnesium strips, tetrahydrofuran, and the 2,3-dimethyl-4-methylthiobromobenzene were mixed, refluxed, and carbon dioxide was introduced to carry out a Grignard reaction to obtain 2,3-methyl-4-methylthiobenzoic acid.

[0009] The 2,3-methyl-4-methylthiobenzoic acid and acetic acid were mixed, and hydrogen peroxide was added to carry out an oxidation reaction to obtain 2,3-dimethyl-4-methanesulfonylbenzoic acid;

[0010] The 2,3-dimethyl-4-methanesulfonylbenzoic acid and methanol were mixed, and thionyl chloride was added to carry out an esterification reaction to obtain methyl 2,3-dimethyl-4-methanesulfonylbenzoate.

[0011] Preferably, the molar ratio of copper powder to 3-amino-o-xylene is (0.6-0.7):1;

[0012] The molar ratio of n-butyl nitrite to 3-aminoo-xylene is 1.1:1;

[0013] The molar ratio of the dimethyl disulfide and 3-amino-o-xylene is (1.0–2.0):1.

[0014] Preferably, the addition temperature of the n-butyl nitrite is 30-35°C;

[0015] The diazotization reaction is carried out at a temperature of 30–35°C for 3–5 hours.

[0016] Preferably, the molar ratio of liquid bromine to 2,3-dimethyl-4-methylthiobenzene is (1.0 to 1.5):1.

[0017] Preferably, the liquid bromine is added at a temperature of 25–30°C;

[0018] The bromination reaction is carried out at a temperature of 25–30°C for 1–2 hours.

[0019] Preferably, the molar ratio of the magnesium strip to 2,3-dimethyl-4-methylthiobromobenzene is (1-1.5):1;

[0020] The molar ratio of carbon dioxide to 2,3-dimethyl-4-methylthiobromobenzene is (3-4):1.

[0021] Preferably, the reflux time is 2-3 hours, and the carbon dioxide inlet temperature is 0-5°C.

[0022] The Grignification reaction is carried out at a temperature of 0–5 °C for 3 hours.

[0023] Preferably, the molar ratio of hydrogen peroxide to 2,3-methyl-4-methylthiobenzoic acid is (2.5-3.5):1;

[0024] The oxidation reaction is carried out at a temperature of 30–50°C for 4–6 hours.

[0025] Preferably, the molar ratio of thionyl chloride to 2,3-dimethyl-4-methanesulfonylbenzoic acid is (1.5-2):1;

[0026] The mass ratio of methanol to 2,3-dimethyl-4-methanesulfonylbenzoic acid is (3-4):1.

[0027] Preferably, the esterification reaction is carried out under reflux conditions for 6 hours.

[0028] This invention provides a method for preparing methyl 2,3-dimethyl-4-methanesulfonylbenzoate, comprising the following steps: mixing copper powder, dimethyl disulfide, and 3-amino-o-xylene, adding n-butyl nitrite, and performing a diazotization reaction to obtain 2,3-dimethyl-4-methylthiobenzene; mixing dichloromethane and the 2,3-dimethyl-4-methylthiobenzene, adding liquid bromine, and performing a bromination reaction to obtain 2,3-dimethyl-4-methylthiobromobenzene; and mixing magnesium strips, tetrahydrofuran, and the 2,3-dimethyl-4-methylthiobenzene... Methyl-4-methylthiobromobenzene is mixed, refluxed, and subjected to a Grignard reaction with carbon dioxide to yield 2,3-methyl-4-methylthiobenzoic acid. The 2,3-methyl-4-methylthiobenzoic acid is then mixed with acetic acid, and hydrogen peroxide is added for oxidation to yield 2,3-dimethyl-4-methanesulfonylbenzoic acid. The 2,3-dimethyl-4-methanesulfonylbenzoic acid is then mixed with methanol, and thionyl chloride is added for esterification to yield methyl 2,3-dimethyl-4-methanesulfonylbenzoate. The preparation method of this invention is simple to operate, the reaction process is easy to control, and it avoids the use of flammable and explosive materials such as n-butyllithium and aluminum chloride. The yield of each reaction step can reach over 95%, the intermediate product selectivity is high, the product purity reaches 97.9%, and the overall yield reaches 87.05%. Detailed Implementation

[0029] This invention provides a method for preparing methyl 2,3-dimethyl-4-methanesulfonylbenzoate, comprising the following steps:

[0030] Copper powder, dimethyl disulfide and 3-amino-o-xylene were mixed, and nitrite was added to carry out a diazotization reaction to obtain 2,3-dimethyl-4-methylthiobenzene;

[0031] Dichloromethane and the 2,3-dimethyl-4-methylthiobenzene were mixed, and liquid bromine was added to carry out a bromination reaction to obtain 2,3-dimethyl-4-methylthiobromobenzene;

[0032] Magnesium strips, tetrahydrofuran, and the 2,3-dimethyl-4-methylthiobromobenzene were mixed, refluxed, and carbon dioxide was introduced to carry out a Grignard reaction to obtain 2,3-methyl-4-methylthiobenzoic acid.

[0033] The 2,3-methyl-4-methylthiobenzoic acid and acetic acid were mixed, and hydrogen peroxide was added to carry out an oxidation reaction to obtain 2,3-dimethyl-4-methanesulfonylbenzoic acid;

[0034] The 2,3-dimethyl-4-methanesulfonylbenzoic acid and methanol were mixed, and thionyl chloride was added to carry out an esterification reaction to obtain methyl 2,3-dimethyl-4-methanesulfonylbenzoate.

[0035] In this invention, unless otherwise specified, all raw materials used in the preparation are commercially available products well known to those skilled in the art.

[0036] In this invention, copper powder, dimethyl disulfide and 3-amino-o-xylene are mixed, and butyl nitrite is added to carry out a diazotization reaction to obtain 2,3-dimethyl-4-methylthiobenzene.

[0037] In this invention, the molar ratio of copper powder to 3-amino-o-xylene is preferably (0.6-0.7):1, more preferably (0.62-0.68):1, and most preferably (0.64-0.66):1; the molar ratio of n-butyl nitrite to 3-amino-o-xylene is preferably 1.1:1; and the molar ratio of dimethyl disulfide to 3-amino-o-xylene is preferably (1.0-2.0):1, more preferably (1.2-1.8):1, and most preferably (1.4-1.6):1.

[0038] In this invention, the mixing is preferably carried out under stirring conditions. This invention does not impose any special limitations on the stirring process; any process well known to those skilled in the art can be used to ensure uniform mixing.

[0039] In this invention, the addition temperature of the n-butyl nitrite is preferably 30-35°C, more preferably 31-34°C, and most preferably 32-33°C; the addition method of the n-butyl nitrite is preferably dropwise addition. This invention does not impose any special limitations on the dropwise addition process, and any process well known to those skilled in the art can be used.

[0040] In this invention, the temperature of the diazotization reaction is preferably 30–35°C, more preferably 31–34°C, and most preferably 32–33°C; the time is preferably 3–5 h, more preferably 3.5–4.5 h. In this invention, the start time of the diazotization reaction is preferably calculated from the completion of the addition of the n-butyl nitrite.

[0041] In this invention, the completion of the diazotization reaction is preferably measured by GC sampling analysis showing that the content of 3-amino-o-xylene is ≤1%.

[0042] After the diazotization reaction is completed, the present invention preferably includes sequential filtration, filtrate desolvation, and vacuum distillation; the present invention does not impose any special limitations on the process of filtration, filtrate desolvation, and vacuum distillation, and any process known to those skilled in the art can be used.

[0043] After obtaining 2,3-dimethyl-4-methylthiobenzene, the present invention mixes dichloromethane and the 2,3-dimethyl-4-methylthiobenzene, adds liquid bromine, and carries out a bromination reaction to obtain 2,3-dimethyl-4-methylthiobromobenzene.

[0044] In this invention, the mass ratio of dichloromethane to 2,3-dimethyl-4-methylthiobenzene is preferably 1:(2-10), more preferably 1:(2-5), and most preferably 1:2. The molar ratio of liquid bromine to 2,3-dimethyl-4-methylthiobenzene is preferably (1.0-1.5):1, more preferably (1.1-1.4):1, and most preferably (1.2-1.3):1.

[0045] In this invention, the mixing is preferably carried out under stirring conditions. This invention does not impose any special limitations on the stirring process; any process well known to those skilled in the art can be used to ensure uniform mixing.

[0046] In this invention, the preferred temperature for adding liquid bromine is 25–30°C, more preferably 26–29°C, and most preferably 27–28°C. In this invention, the preferred method for adding liquid bromine is dropwise addition. This invention does not impose any special limitations on the dropwise addition process; any dropwise addition process well-known to those skilled in the art can be used.

[0047] In this invention, the temperature of the bromination reaction is preferably 25–30°C, more preferably 26–29°C, and most preferably 27–28°C; the time is preferably 1–2 h, more preferably 1.2–1.8 h, and most preferably 1.4–1.6 h. The start time of the bromination reaction is preferably calculated from the completion of the addition of liquid bromine.

[0048] In this invention, the completion of the bromination reaction is preferably measured by HPLC to determine that the content of 2,3-dimethyl-4-methylthiobenzene is ≤1%.

[0049] After the bromination reaction is completed, the present invention preferably includes adding a saturated sodium sulfite solution to the obtained product system, stirring evenly, allowing it to stand and separate into layers, separating the organic phase, washing it with water three times, combining the organic phases, and removing the solvent.

[0050] After obtaining 2,3-dimethyl-4-methylthiobromobenzene, the present invention mixes magnesium strips, tetrahydrofuran and the 2,3-dimethyl-4-methylthiobromobenzene, refluxes the mixture, and introduces carbon dioxide to carry out a Grignard reaction to obtain 2,3-methyl-4-methylthiobenzoic acid.

[0051] In this invention, the molar ratio of the magnesium strip to 2,3-dimethyl-4-methylthiobromobenzene is preferably (1-1.5):1, more preferably (1.1-1.4):1, and most preferably (1.2-1.3):1; the molar ratio of the carbon dioxide to 2,3-dimethyl-4-methylthiobromobenzene is preferably (3-4):1, more preferably (3.2-3.8):1, and most preferably (3.4-3.6):1; the mass ratio of the tetrahydrofuran to 2,3-dimethyl-4-methylthiobromobenzene is preferably 1:(5-10), more preferably 1:(5-8), and most preferably 1:5.

[0052] In this invention, the mixing is preferably carried out under stirring conditions. This invention does not impose any special limitations on the stirring process, and any process well known to those skilled in the art can be used.

[0053] In this invention, the temperature is preferably raised to the reflux temperature under stirring conditions. In this invention, the reflux time is preferably 2–3 hours, more preferably 2.2–2.8 hours, and most preferably 2.4–2.6 hours.

[0054] In this invention, the stirring is preferably completed when the content of 2,3-dimethyl-4-methylthiobromobenzene in the reaction system is ≤1%.

[0055] After the reflux is completed, the present invention preferably includes cooling. The present invention does not have any special limitations on the cooling process, as long as the temperature is reduced to 0-5°C.

[0056] In this invention, the preferred temperature for introducing carbon dioxide is 0–5°C; the preferred temperature for the Grignard reaction is 0–5°C, and the preferred time is 3 hours.

[0057] After the Grignardization reaction is completed, the present invention preferably includes adding a 10% hydrochloric acid solution to the obtained product system for quenching, removing tetrahydrofuran under reduced pressure, adding water and stirring for 1 hour, and then sequentially filtering and drying.

[0058] After obtaining 2,3-methyl-4-methylthiobenzoic acid, the present invention mixes the 2,3-methyl-4-methylthiobenzoic acid with acetic acid, adds hydrogen peroxide, and carries out an oxidation reaction to obtain 2,3-dimethyl-4-methanesulfonylbenzoic acid.

[0059] In this invention, the mass ratio of 2,3-methyl-4-methylthiobenzoic acid to acetic acid is preferably 1:(2-5), more preferably 1:(2-3), and most preferably 1:2; the molar ratio of hydrogen peroxide to 2,3-methyl-4-methylthiobenzoic acid is preferably (2.5-3.5):1, more preferably (2.8-3.2):1, and most preferably (2.9-3.1):1.

[0060] In this invention, the mixing is preferably carried out under stirring conditions. This invention does not impose any special limitations on the stirring process, and any process well known to those skilled in the art can be used.

[0061] In this invention, the hydrogen peroxide is preferably added by dripping. This invention does not impose any special limitations on the dripping process, and any process known to those skilled in the art can be used.

[0062] In this invention, the temperature of the oxidation reaction is preferably 30-50°C, more preferably 35-45°C, and most preferably 38-42°C; the time is preferably 4-6 hours, more preferably 4.5-5.5 hours, and most preferably 4.8-5.2 hours.

[0063] In this invention, the oxidation reaction is preferably completed when the content of 2,3-methyl-4-methylthiobenzoic acid in the reaction system is ≤1%.

[0064] After the oxidation reaction is completed, the present invention preferably includes sequentially cooling to 25°C, stirring for 2 hours, filtration, washing with water, and drying. The present invention does not impose any special limitations on the cooling, stirring, filtration, washing with water, and drying processes, and any process known to those skilled in the art can be used.

[0065] After obtaining 2,3-dimethyl-4-methanesulfonylbenzoic acid, the present invention mixes the 2,3-dimethyl-4-methanesulfonylbenzoic acid with methanol, adds thionyl chloride, and carries out an esterification reaction to obtain methyl 2,3-dimethyl-4-methanesulfonylbenzoate.

[0066] In this invention, the molar ratio of thionyl chloride to 2,3-dimethyl-4-methanesulfonylbenzoic acid is preferably (1.5-2):1, more preferably (1.6-1.9):1, and most preferably (1.7-1.8):1; the mass ratio of methanol to 2,3-dimethyl-4-methanesulfonylbenzoic acid is preferably (3-4):1, more preferably (3.2-3.8):1, and most preferably (3.4-3.6):1.

[0067] In this invention, the mixing is preferably carried out under stirring conditions. This invention does not impose any special limitations on the stirring process, and any process well known to those skilled in the art can be used.

[0068] In this invention, the addition of thionyl chloride is preferably carried out under reflux conditions, and the addition method of thionyl chloride is preferably dropwise. This invention does not impose any special limitations on the dropwise addition process, and any process well known to those skilled in the art can be used.

[0069] The esterification reaction is preferably completed when the content of 2,3-dimethyl-4-methanesulfonylbenzoic acid in the reaction system is ≤1%.

[0070] Following the esterification reaction, the present invention preferably further includes sequentially cooling to room temperature and removing methanol under reduced pressure; the present invention does not impose any special limitations on the cooling and depressurization process, and any process well known to those skilled in the art can be used.

[0071] The preparation method of methyl 2,3-dimethyl-4-methanesulfonylbenzoate provided by the present invention will be described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0072] Example 1

[0073] Preparation of 2,3-dimethyl-4-methylthiobenzene (denoted as Top-B):

[0074] 249.2 g of 2,3-dimethylaniline (2.038 mol, 1 eq), 857.3 g of dimethyl disulfide (9.025 mol, 4.43 eq), and 82.1 g of copper powder (1.29 mol, 0.63 eq) were added to a 2 L reaction flask. Under stirring, 243.29 g of butyl nitrite (2.24 mol, 1.1 eq) was slowly added dropwise. The temperature of the adding device was controlled at 55 °C. After the addition was completed within 3 hours, the mixture was kept at this temperature for 30 minutes. GC analysis was performed until the raw material content was ≤1%, at which point the reaction was stopped. The mixture was then desolvated under reduced pressure using a water pump to recover dimethyl disulfide and butyl nitrite. After desolvation, the mixture was distilled using an oil pump to obtain 2,3-dimethyl-4-methylthiobenzene (309.7 g, purity 95.0%, yield 95%). 1 H NMR: δ2.32(3H),2.33(3H),2.50(3H),7.43(1H),7.45(1H),7.21(1H);

[0075] Preparation of 2,3-dimethyl-4-methylthiobromobenzene (denoted as Top-C):

[0076] 700g of 2,3-dimethylbenzene sulfide (Top-B) (4.48mol, 1eq) and 2800g of dichloromethane were added to a four-necked flask. Under stirring, 868.8g of liquid bromine (5.38mol, 1.2eq) was added dropwise. The reaction temperature was controlled at 35℃. After the addition was completed and the temperature was maintained for 1h, a sample was taken. The Top-B content was detected by high performance liquid chromatography until the reaction was completed. 300g of saturated sodium sulfite aqueous solution was added, stirred, and washed twice with water (400mL / time). The aqueous layer was separated by standing, weighed, and the sample was measured. The organic layer was desolvated to obtain the 2,3-dimethyl-4-methylthiobromobenzene (1033.01g, content 97.6%, yield 97.7%). 1 H NMR: δ2.43(3H),2.33(3H),2.50(3H),7.76(1H),7.79(1H);

[0077] Preparation of 2,3-methyl-4-methylthiobenzoic acid (Top-1):

[0078] 10.6 g Mg (0.44 mol, 2.0 eq), 300 g THF and 50 g Top-C (0.22 mol, 1.0 eq) were added to a dry reaction flask and stirred until homogeneous. The mixture was purged with nitrogen three times and heated to reflux under nitrogen protection. The mixture was kept under reflux for 5 h. TLC analysis was performed until the starting material disappeared. The mixture was then cooled to 0 °C and CO2 was bubbled through the flask. TLC sampling was performed to monitor the reaction. After the starting material disappeared, 10% hydrochloric acid solution was added to quench the reaction. A large amount of solid precipitated out. The solid was filtered to obtain the wet product of 2,3-methyl-4-methylthiobenzoic acid. The product was dried at 70 °C for 6 h to obtain 2,3-methyl-4-methylthiobenzoic acid (44.67 g, purity 94.6%, yield 98.0%). 1 H NMR: δ2.43(3H),2.33(3H),3.22(3H),7.76(1H),7.79(1H);

[0079] Preparation of 2,3-dimethyl-4-methanesulfonylbenzoic acid (Top-2):

[0080] 100g of Top-1 (0.48mol, 1eq) and 500g of acetic acid were added to a reaction flask and stirred until homogeneous. The mixture was heated to 30°C, and 154.8g of 27.5% hydrogen peroxide (1.44mol, 3.0eq) was slowly added dropwise while maintaining the temperature between 35°C and 35°C. After the addition was complete, the mixture was kept at this temperature for 2 hours. A sample was taken and tested until the Top-1 content was ≤1%. The mixture was then cooled to 25°C and stirred for 2 hours. The mixture was then filtered and washed with water to obtain 131.4g of the product. After drying, 107.76g of 2,3-dimethyl-4-methanesulfonylbenzoic acid (content 97.9%, yield 96.4%) was obtained. 1H NMR: δ2.35(3H),2.33(3H),3.22(3H),7.76(1H),7.51(1H),11.20(1H);

[0081] Preparation of methyl 2,3-dimethyl-4-methanesulfonylbenzoate (Top-3):

[0082] 100g of the aforementioned Top-2 (0.429mol, 1eq) and 300g of methanol were added to a reaction flask, stirred until homogeneous, heated to reflux, and 117.7g of thionyl chloride (0.98mol, 2.0eq) was slowly added dropwise. The reaction was maintained at this temperature for 6 hours. Samples were taken to check the Top-2 content until it was ≤1%. The mixture was cooled to room temperature, and methanol was removed under reduced pressure to obtain the aforementioned methyl 2,3-dimethyl-4-methanesulfonylbenzoate (105.9g, content 96.6%, yield 98.4%). 1 H NMR: δ3.72(3H), 2.35(3H), 2.33(3H), 3.22(3H), 7.76(1H), 7.51(1H).

[0083] Example 2

[0084] Preparation of 2,3-dimethyl-4-methylthiobenzene (denoted as Top-B):

[0085] 500 g of 2,3-dimethylaniline (4.09 mol, 1 eq), 1703 g of dimethyl disulfide (18.1 mol, 4.43 eq), and 163.6 g of copper powder (2.57 mol, 0.63 eq) were added to a 2 L reaction flask. 487.7 g of butyl nitrite (5.7 mol, 1.1 eq) was slowly added dropwise under stirring. The temperature of the dropwise addition device was controlled at 45 °C. After the addition was completed within 3 hours, the mixture was kept at this temperature for 30 minutes. GC analysis was performed until the raw material content was ≤1%, at which point the reaction was stopped. The mixture was then desolvated under reduced pressure using a water pump to recover dimethyl disulfide and butyl nitrite. After desolvation, the mixture was distilled using an oil pump to obtain 2,3-dimethyl-4-methylthiobenzene (634.7 g, 95.0% purity, 97% yield).

[0086] Preparation of 2,3-dimethyl-4-methylthiobromobenzene (denoted as Top-C):

[0087] 500g of 2,3-dimethylbenzene sulfide (Top-B) (3.125mol, 1eq) and 1000g of dichloromethane were added to a four-necked flask. Under stirring, 555.5g of liquid bromine (3.43mol, 1.1eq) was added dropwise. The reaction temperature was controlled at 40℃. After the addition was completed and the temperature was maintained for 1h, a sample was taken. The Top-B content was detected by high performance liquid chromatography until the reaction was completed. 200g of saturated sodium sulfite aqueous solution was added, stirred, and washed twice with water (200mL / time). The aqueous layer was separated by standing, weighed, and the sample was measured. The organic layer was desolventized to obtain the 2,3-dimethyl-4-methylthiobromobenzene (727.08g, content 97.6%, yield 97.7%).

[0088] Preparation of 2,3-methyl-4-methylthiobenzoic acid (Top-1):

[0089] 20.12 g Mg (0.88 mol, 2.0 eq), 600 g THF and 100 g Top-C (0.44 mol, 1.0 eq) were added to a dry reaction flask and stirred until homogeneous. The mixture was purged with nitrogen three times and heated to reflux under nitrogen protection. The mixture was kept under reflux for 5 h. TLC analysis was performed until the starting material disappeared. The mixture was then cooled to 0 °C and CO2 was bubbled through the flask. TLC sampling was performed to monitor the reaction. After the starting material disappeared, 10% hydrochloric acid solution was added to quench the reaction, resulting in the precipitation of a large amount of solid. The solid was filtered to obtain 111.72 g of wet 2,3-methyl-4-methylthiobenzoic acid. The product was dried at 70 °C for 6 h to obtain 89.34 g of 2,3-methyl-4-methylthiobenzoic acid (purity 94.6%, yield 98.0%).

[0090] Preparation of 2,3-dimethyl-4-methanesulfonylbenzoic acid (Top-2):

[0091] Add 50g of Top-1 (0.24mol, 1eq) and 500g of acetic acid to a reaction flask and stir until homogeneous. Heat to 30°C and slowly add 77.4g of 27.5% hydrogen peroxide (7.2mol, 3.0eq) while maintaining the temperature at 40°C. After the addition is complete, keep warm for 3 hours. Take a sample and check if the Top-1 content is ≤1%. Cool down to 25°C and stir for 2 hours. Filter and wash with water sequentially to obtain 67.05g. Dry to obtain 2,3-dimethyl-4-methanesulfonylbenzoic acid (53.88g, content 97.9%, yield 96.4%).

[0092] Preparation of methyl 2,3-dimethyl-4-methanesulfonylbenzoate (Top-3):

[0093] Add 50g of the aforementioned Top-2 (0.2145mol, 1eq) and 300g of methanol to a reaction flask, stir until homogeneous, heat to reflux, and slowly add 58.85g of thionyl chloride (0.429mol, 2.0eq). Maintain the reaction temperature for 6h, take a sample to check the Top-2 content until it is ≤1%, cool to room temperature, remove methanol under reduced pressure to obtain the aforementioned methyl 2,3-dimethyl-4-methanesulfonylbenzoate (52.95g, content 96.6%, yield 98.4%).

[0094] Example 3

[0095] Preparation of 2,3-dimethyl-4-methylthiobenzene (denoted as Top-B):

[0096] 700 g of 2,3-dimethylaniline (5.72 mol, 1 eq), 2221.8 g of dimethyl disulfide (23.4 mol, 4.1 eq), and 146.9 g of copper powder (2.28 mol, 0.63 eq) were added to a 2 L reaction flask. 682.1 g of butyl nitrite (6.2921 mol, 1.1 eq) was slowly added dropwise under stirring. The temperature of the dropwise addition device was controlled at 55 °C. After the addition was completed within 3 hours, the mixture was kept at this temperature for 30 minutes. GC analysis was performed until the raw material content was ≤1%, at which point the reaction was stopped. The mixture was then desolvated under reduced pressure using a water pump to recover dimethyl disulfide and butyl nitrite. After desolvation, the mixture was distilled using an oil pump to obtain 2,3-dimethyl-4-methylthiobenzene (309.7 g, 95.0% purity, 95% yield).

[0097] Preparation of 2,3-dimethyl-4-methylthiobromobenzene (denoted as Top-C):

[0098] 700g of 2,3-dimethylbenzene sulfide (Top-B) (4.48mol, 1eq) and 1400g of dichloromethane were added to a four-necked flask. Under stirring, 493.4g of liquid bromine (5.38mol, 1.2eq) was added dropwise. The reaction temperature was controlled at 45℃. After the addition was completed and the temperature was maintained for 1 hour, a sample was taken. The Top-B content was detected by high performance liquid chromatography until the reaction was completed. 300g of saturated sodium sulfite aqueous solution was added, stirred, and washed twice with water (400mL / time). The aqueous layer was separated by standing, weighed, and the sample was measured. The organic layer was desolventized to obtain the 2,3-dimethyl-4-methylthiobromobenzene (1026.29g, content 96.4%, yield 95.6%).

[0099] Preparation of 2,3-methyl-4-methylthiobenzoic acid (Top-1):

[0100] In a dry reaction flask, 31.8 g of Mg (1.32 mol, 2.0 eq), 900 g of THF, and 150 g of the aforementioned Top-C (0.66 mol, 1.0 eq) were added and stirred until homogeneous. The mixture was purged with nitrogen three times, and the temperature was raised to reflux under nitrogen protection. The mixture was kept at reflux for 5 h. TLC analysis was performed until the starting material disappeared. The temperature was then lowered to 0 °C, and CO2 was bubbled through the mixture. TLC sampling was performed to monitor the reaction. After the starting material spot disappeared, 10% hydrochloric acid solution was added to quench the reaction, resulting in the precipitation of a large amount of solid. The solid was filtered to obtain 167.49 g of wet 2,3-methyl-4-methylthiobenzoic acid. The solid was dried at 70 °C for 6 h to obtain 134.1 g of 2,3-methyl-4-methylthiobenzoic acid (purity 94.6%, yield 98.0%).

[0101] Preparation of 2,3-dimethyl-4-methanesulfonylbenzoic acid (Top-2):

[0102] 10g of the aforementioned Top-1 (0.048mol, 1eq) and 500g of acetic acid were added to a reaction flask and stirred until homogeneous. The mixture was heated to 30°C, and 15.48g of 27.5% hydrogen peroxide (0.144mol, 3.0eq) was slowly added dropwise while maintaining the temperature at 45°C. After the addition was complete, the mixture was kept at this temperature for 3 hours. A sample was taken and tested until the Top-1 content was ≤1%. The mixture was then cooled to 25°C and stirred for 2 hours. The mixture was then filtered and washed with water to obtain 13.14g of the product. After drying, the 2,3-dimethyl-4-methanesulfonylbenzoic acid (10.776g, content 97.9%, yield 96.4%) was obtained.

[0103] Preparation of methyl 2,3-dimethyl-4-methanesulfonylbenzoate (Top-3):

[0104] 10g of the aforementioned Top-2 (0.0429mol, 1eq) and 30g of methanol were added to a reaction flask, stirred until homogeneous, heated to reflux, and 11.77g of thionyl chloride (0.098mol, 2.0eq) was slowly added dropwise. The reaction was maintained at this temperature for 6h. Samples were taken to check the Top-2 content until it was ≤1%. The mixture was cooled to room temperature, and methanol was removed under reduced pressure to obtain the aforementioned methyl 2,3-dimethyl-4-methanesulfonylbenzoate (10.59g, purity 96.6%, yield 98.4%).

[0105] Comparative Example 1

[0106] Refer to Example 1, except for the preparation method of 2,3-methyl-4-methylthiobenzoic acid (Top-1):

[0107] 10.6 g Mg (0.44 mol, 2.0 eq), 300 g THF and 50 g Top-C (0.22 mol, 1.0 eq) were added to a dry reaction flask and stirred until homogeneous. The mixture was purged with nitrogen three times and heated to reflux under nitrogen protection. The mixture was kept under reflux for 5 h. TLC analysis was performed until the starting material disappeared. The mixture was then cooled to 5 °C and CO2 was bubbled through the flask. TLC sampling was performed to monitor the reaction. After the starting material disappeared, 10% hydrochloric acid solution was added to quench the reaction, resulting in the precipitation of a large amount of solid. The solid was filtered to obtain the wet product of 2,3-methyl-4-methylthiobenzoic acid. The product was dried at 70 °C for 6 h to obtain 2,3-methyl-4-methylthiobenzoic acid (40.5 g, purity 89.6%, yield 84.2%).

[0108] Comparative Example 2

[0109] Refer to Example 1, except for the preparation method of 2,3-methyl-4-methylthiobenzoic acid (Top-1):

[0110] 10.6 g Mg (0.44 mol, 2.0 eq), 300 g THF and 50 g Top-C (0.22 mol, 1.0 eq) were added to a dry reaction flask and stirred until homogeneous. The mixture was purged with nitrogen three times and heated to reflux under nitrogen protection. The mixture was kept under reflux for 5 h. TLC analysis was performed until the starting material disappeared. The mixture was then cooled to 10 °C and CO2 was bubbled through the flask. TLC sampling was performed to monitor the reaction. After the starting material disappeared, 10% hydrochloric acid solution was added to quench the reaction, resulting in the precipitation of a large amount of solid. The solid was filtered to obtain the wet product of 2,3-methyl-4-methylthiobenzoic acid. The product was dried at 70 °C for 6 h to obtain 2,3-methyl-4-methylthiobenzoic acid (33.2 g, purity 69.2%, yield 71%).

[0111] Comparative Example 3

[0112] 700 g of 2,3-dimethylanisole (Top-B) (4.48 mol, 1 eq) and 1400 g of dichloromethane were added to a four-necked flask. Under stirring, 493.4 g of liquid bromine (5.38 mol, 1.05 eq) was added dropwise. The reaction temperature was controlled at 45°C. After the addition was complete and the mixture was kept at this temperature for 1 hour, a sample was taken. High-performance liquid chromatography (HPLC) analysis showed that Top-B was <1% until the reaction was complete. 300 g of saturated sodium sulfite aqueous solution was added, and the mixture was stirred and washed twice with water (400 mL each time). The aqueous layer was allowed to stand, the sample was weighed, and the organic layer was dissolved to obtain 736.15 g of 2,3-dimethyl-4-methylthiobromobenzene (purity 96.4%, yield 69%).

[0113] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing methyl 2,3-dimethyl-4-methanesulfonylbenzoate, characterized in that, Includes the following steps: Copper powder, dimethyl disulfide, and 3-amino-o-xylene were mixed, and butyl nitrite was added to carry out a diazotization reaction. The mixture was then subjected to suction filtration, solvent removal from the filtrate, and vacuum distillation to obtain 2,3-dimethyl-1-thiomethylbenzene. The molar ratio of copper powder to 3-amino-o-xylene was (0.6~0.7):1; the molar ratio of butyl nitrite to 3-amino-o-xylene was 1.1:1; the molar ratio of dimethyl disulfide to 3-amino-o-xylene was (1.0~2.0):1; the addition temperature of butyl nitrite was 30~35℃; and the reaction temperature was 30~35℃ for 3~5 hours. Dichloromethane and the 2,3-dimethyl-1-thiomethylbenzene were mixed, liquid bromine was added, and after bromination, saturated sodium sulfite solution was added and stirred evenly. The mixture was allowed to stand and separate into layers, the organic phase was separated, washed three times with water, the organic phases were combined, and the solvent was removed to obtain 2,3-dimethyl-4-methylthiobromobenzene. Magnesium strips, tetrahydrofuran, and the 2,3-dimethyl-4-methylthiobromobenzene were mixed, refluxed, and carbon dioxide was introduced to carry out the Grignard reaction. A 10% hydrochloric acid solution was added to the obtained product system for quenching. After removing the tetrahydrofuran under reduced pressure, water was added and stirred for 1 hour. The mixture was then filtered and dried to obtain 2,3-dimethyl-4-methylthiobenzoic acid. The 2,3-dimethyl-4-methylthiobenzoic acid and acetic acid were mixed, hydrogen peroxide was added, and an oxidation reaction was carried out. The mixture was cooled to 25°C and stirred for 2 hours. The mixture was then filtered, washed with water, and dried to obtain 2,3-dimethyl-4-methanesulfonylbenzoic acid. The molar ratio of hydrogen peroxide to 2,3-dimethyl-4-methylthiobenzoic acid was (2.5~3.5):

1. The oxidation reaction was carried out at a temperature of 30~50°C for 4~6 hours. The 2,3-dimethyl-4-methanesulfonylbenzoic acid and methanol were mixed, and thionyl chloride was added to carry out an esterification reaction. The mixture was then cooled to room temperature and the methanol was removed under reduced pressure to obtain methyl 2,3-dimethyl-4-methanesulfonylbenzoate. The molar ratio of thionyl chloride to 2,3-dimethyl-4-methanesulfonylbenzoic acid was (1.5~2):

1. The mass ratio of methanol to 2,3-dimethyl-4-methanesulfonylbenzoic acid was (3~4):

1. The esterification reaction was carried out under reflux for 6 hours.

2. The preparation method according to claim 1, characterized in that, The molar ratio of liquid bromine to 2,3-dimethyl-1-thiomethylbenzene is (1.0~1.5):

1.

3. The preparation method according to claim 1 or 2, characterized in that, The liquid bromine is added at a temperature of 25~30℃; The bromination reaction is carried out at a temperature of 25-30°C for 1-2 hours.

4. The preparation method according to claim 1, characterized in that, The molar ratio of the magnesium strip to 2,3-dimethyl-4-methylthiobromobenzene is (1~1.5):1; The molar ratio of carbon dioxide to 2,3-dimethyl-4-methylthiobromobenzene is (3~4):

1.

5. The preparation method according to claim 1 or 4, characterized in that, In the Grignardization reaction, the reflux time is 2-3 hours, and the carbon dioxide is introduced at a temperature of 0-15°C. The Grignification reaction is carried out at a temperature of 0-5°C for 3 hours.