A method for preparing methyl 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate

Abstract

This invention relates to the field of organic synthesis technology, and more particularly to a method for preparing methyl 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate. The preparation method of this invention uses 3-amino-o-xylene as a starting material, and sequentially proceeds through diazotization of the methylthio group, bromination, Grignard carboxylation, oxidation, esterification, bromination, oxidation, oxime formation, chlorination, and 1,3-dipolar addition to ethylene. The preparation method is simple to operate, has good selectivity for unit reactions, high yield, low cost, and readily available raw materials.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing methyl 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate. Background Technology

[0002] Benzoflubenzuron is the first benzyl pyrazolone herbicide, belonging to the class of 4-HPPD inhibitors. It exhibits excellent control of weeds resistant to glyphosate, triazine, acetolactate synthase (ALS) inhibitors, and acetyl-CoA carboxylase (ACCase) inhibitors, making it a broad-spectrum post-emergence herbicide. Its compound annual growth rate (CAGR) from 2009 to 2014 was 33.6%.

[0003] US Patent US614703A1 discloses the synthesis of 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoic acid from methyl 2,3-dimethyl-4-methanesulfonylbenzoate as a starting material. A drawback of this method is that the starting material methyl 2,3-dimethyl-4-methanesulfonylbenzoate is difficult to obtain commercially. Chinese Patent CN110922367A (Jiangsu Zhongqi Technology Co., Ltd.) discloses a method involving the cyanidation reaction of 3-[3-bromo-2-methyl-6-(methanesulfonyl)phenyl]-4,5-dihydroisoxazole with cuprous cyanide, followed by hydrolysis with NaOH to obtain 2... 2-Methyl-3-(4,5-dihydroisoxazol-3-yl)-4-methanesulfonylbenzoic acid is synthesized using 3-nitro-o-xylene as a raw material through oxime reaction, ethylene ring closure, palladium reduction on carbon, diazotization, aldehyde oxidization, and oxidation. The drawback of this method is that it uses n-butyllithium salt, the reaction conditions are harsh, requiring anhydrous and oxygen-free conditions, and the reaction temperature must be -78℃, which is difficult to achieve but can be industrialized on a large scale. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing methyl 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate. The preparation method is simple to operate, has good reaction selectivity, high yield, low cost, and the raw materials are readily available.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0006] This invention provides a method for preparing methyl 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate, comprising the following steps:

[0007] Copper powder, dimethyl disulfide and 3-amino-o-xylene were mixed and then nitrite was added to carry out a diazotization reaction to obtain 2,3-dimethyl-4-methylthiobenzene.

[0008] The 2,3-dimethyl-4-methylthiobenzene and dichloromethane were mixed and then liquid bromine was added to carry out the first bromination reaction to obtain 2,3-dimethyl-4-methylthiobromobenzene;

[0009] The 2,3-dimethyl-4-methylthiobromobenzene, magnesium and tetrahydrofuran were mixed and refluxed for Grignard carboxylation. Then carbon dioxide was introduced for Grignardization to obtain 2,3-methyl-4-methylthiobenzoic acid.

[0010] The 2,3-methyl-4-methylthiobenzoic acid and acetic acid were mixed, and hydrogen peroxide was added to carry out the first oxidation reaction to obtain 2,3-dimethyl-4-methanesulfonylbenzoic acid;

[0011] 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.

[0012] The methyl 2,3-dimethyl-4-methanesulfonylbenzoate, carbon tetrachloride, benzoyl peroxide and N-bromosuccinimide were mixed and refluxed to carry out a second bromination reaction to obtain methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate.

[0013] The methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate was mixed with acetonitrile, cooled, and N-methylmorpholine oxide was added to carry out a second oxidation reaction to obtain methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate.

[0014] The methyl 3-formyl-2-methyl-4-methylsulfonyl benzoate, hydroxylamine hydrochloride, and ethanol were mixed and refluxed to undergo an oxime reaction to obtain methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate;

[0015] The methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate was mixed with dichloromethane, and then N-chlorosuccinimide was added for chlorination. Triethylamine was added, and nitrogen gas and ethylene were successively introduced for displacement and dipole addition reaction to obtain the methyl 3-(4,5-dihydro-3-isooxazolyl)-2-methyl-4-methylsulfonylbenzoate.

[0016] Preferably, the molar ratio of copper powder to 3-amino-o-xylene is (0.6-0.7):1;

[0017] The molar ratio of n-butyl nitrite to 3-aminoo-xylene is 1.1:1;

[0018] The molar ratio of the dimethyl disulfide and 3-amino-o-xylene is (1.0–2.0):1.

[0019] Preferably, the diazotization reaction is carried out at a temperature of 30–35°C for 3–5 hours.

[0020] Preferably, the molar ratio of 2,3-dimethyl-4-methylthiobenzene to liquid bromine is 1:(1.0 to 1.5).

[0021] Preferably, the molar ratio of 2,3-dimethyl-4-methylthiobromobenzene to magnesium is 1:(1-1.5);

[0022] The molar ratio of 2,3-dimethyl-4-methylthiobromobenzene to carbon dioxide is 1:(3-4).

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

[0024] Preferably, the molar ratio of methyl 2,3-dimethyl-4-methanesulfonylbenzoate to N-bromosuccinimide is 1:(1.1 to 1.5);

[0025] The mass ratio of methyl 2,3-dimethyl-4-methanesulfonylbenzoate to benzoyl peroxide is 1:(0.1-1.0).

[0026] The volume ratio of methyl 2,3-dimethyl-4-methanesulfonylbenzoate to carbon tetrachloride is 5:1.

[0027] Preferably, the molar ratio of N-methylmorpholine oxide to methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate is (1.5-2.5):1;

[0028] The mass ratio of acetonitrile to methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate is 5:1.

[0029] Preferably, the molar ratio of methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate to hydroxylamine hydrochloride is 1:(1.1 to 1.5).

[0030] The mass ratio of methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate to ethanol is 1:(3-5).

[0031] Preferably, the molar ratio of methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate to N-chlorosuccinimide is 1:(1.1-1.5).

[0032] The mass ratio of methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate to dichloromethane is 1:(3-5).

[0033] This invention provides a method for preparing methyl 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate, 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 the 2,3-dimethyl-4-methylthiobenzene with dichloromethane, adding liquid bromine, and performing a first bromination reaction to obtain 2,3-dimethyl-4-methylthiobromobenzene; and preparing the 2,3-dimethyl-4-methylthiobromobenzene... A mixture of methyl bromide, magnesium, and tetrahydrofuran is refluxed for Grignard carboxylation, followed by Grignardization 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 a first oxidation reaction 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. 2,3-Dimethyl-4-methanesulfonylbenzoate, carbon tetrachloride, benzoyl peroxide, and N-bromosuccinimide were mixed and refluxed for a second bromination reaction to obtain methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate. The methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate was then mixed with acetonitrile, cooled, and N-methylmorpholine oxide was added for a second oxidation reaction to obtain methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate. The methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate was then... The ester, hydroxylamine hydrochloride, and ethanol were mixed and refluxed to undergo an oxime reaction to obtain methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methanesulfonyl)benzoate; the methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methanesulfonyl)benzoate was mixed with dichloromethane, and N-chlorosuccinimide was added for chlorination. Triethylamine was added, and nitrogen gas and ethylene were successively introduced for dipolar addition reaction to obtain methyl 3-(4,5-dihydro-3-isooxazolyl)-2-methyl-4-methylsulfonylbenzoate. The preparation method of the present invention uses 3-amino-o-xylene as the starting material and proceeds sequentially through diazotization of methylthio, bromination, Grignard carboxylation, oxidation, esterification, bromination, oxidation, oximeation, chlorination, and ethylene 1,3-dipolar addition. The preparation method is simple to operate, has good selectivity of unit reactions, high yield, low cost, and the raw materials are readily available. Detailed Implementation

[0034] This invention provides a method for preparing methyl 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate, comprising the following steps:

[0035] Copper powder, dimethyl disulfide and 3-amino-o-xylene were mixed and then nitrite was added to carry out a diazotization reaction to obtain 2,3-dimethyl-4-methylthiobenzene.

[0036] The 2,3-dimethyl-4-methylthiobenzene and dichloromethane were mixed and then liquid bromine was added to carry out the first bromination reaction to obtain 2,3-dimethyl-4-methylthiobromobenzene;

[0037] The 2,3-dimethyl-4-methylthiobromobenzene, magnesium and tetrahydrofuran were mixed and refluxed for Grignard carboxylation. Then carbon dioxide was introduced for Grignardization to obtain 2,3-methyl-4-methylthiobenzoic acid.

[0038] The 2,3-methyl-4-methylthiobenzoic acid and acetic acid were mixed, and hydrogen peroxide was added to carry out the first oxidation reaction to obtain 2,3-dimethyl-4-methanesulfonylbenzoic acid;

[0039] 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.

[0040] The methyl 2,3-dimethyl-4-methanesulfonylbenzoate, carbon tetrachloride, benzoyl peroxide and N-bromosuccinimide were mixed and refluxed to carry out a second bromination reaction to obtain methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate.

[0041] The methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate was mixed with acetonitrile, cooled, and N-methylmorpholine oxide was added to carry out a second oxidation reaction to obtain methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate.

[0042] The methyl 3-formyl-2-methyl-4-methylsulfonyl benzoate, hydroxylamine hydrochloride, and ethanol were mixed and refluxed to undergo an oxime reaction to obtain methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate;

[0043] The methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate was mixed with dichloromethane, and then N-chlorosuccinimide was added for chlorination. Triethylamine was added, and nitrogen gas and ethylene were successively introduced for displacement and dipole addition reaction to obtain the methyl 3-(4,5-dihydro-3-isooxazolyl)-2-methyl-4-methylsulfonylbenzoate.

[0044] 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.

[0045] In this invention, copper powder, dimethyl disulfide and 3-amino-o-xylene are mixed and then nitrite n-butyl ester is added to carry out a diazotization reaction to obtain 2,3-dimethyl-4-methylthiobenzene.

[0046] 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 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.

[0047] In this invention, the mixing is preferably carried out under stirring conditions, the stirring temperature is preferably 30-35°C, more preferably 32-33°C, and the stirring time is preferably 0.5-5h, more preferably 0.5-2h, and most preferably 1-2h.

[0048] In this invention, the addition of n-butyl nitrite is preferably by dripping. This invention does not impose any special limitations on the dripping process, and any process well known to those skilled in the art can be used.

[0049] In this invention, the molar ratio of n-butyl nitrite to 3-amino-o-xylene is preferably 1.1:1.

[0050] 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, and most preferably 3.8-4.2 h.

[0051] In this invention, the diazotization reaction is preferably terminated when the content of 3-amino-o-xylene is preferably ≤1% as determined by GC sampling analysis.

[0052] 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.

[0053] After obtaining 2,3-dimethyl-4-methylthiobenzene, the present invention mixes the 2,3-dimethyl-4-methylthiobenzene with dichloromethane, adds liquid bromine, and carries out a first bromination reaction to obtain 2,3-dimethyl-4-methylthiobromobenzene.

[0054] In this invention, the volume ratio of 2,3-dimethyl-4-methylthiobenzene to dichloromethane is preferably 1:(2-10), more preferably 1:(2-5), and most preferably 1:2.

[0055] 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.

[0056] In this invention, the liquid bromine is preferably added by dripping, and the dripping temperature is preferably 25-30°C, more preferably 26-28°C. 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.

[0057] In this invention, the molar ratio of 2,3-dimethyl-4-methylthiobenzene to liquid bromine is preferably 1:(1.0-1.5), more preferably 1:(1.1-1.4), and most preferably 1:(1.2-1.3).

[0058] In this invention, the temperature of the first bromination reaction is preferably 25-30°C, more preferably 26-28°C; the time is preferably 1-2 hours, more preferably 1.2-1.8 hours, and most preferably 1.4-1.6 hours.

[0059] In this invention, the first bromination reaction is preferably terminated when the content of Top-B, as determined by HPLC sampling analysis, is preferably ≤1%.

[0060] After the first bromination reaction is completed, the present invention preferably includes adding a saturated sodium sulfite solution to the obtained product system, stirring until homogeneous, allowing it to stand and separate into layers to separate the organic phase, washing with water three times, combining the organic phases, and removing the solvent.

[0061] After obtaining 2,3-dimethyl-4-methylthiobromobenzene, the present invention mixes the 2,3-dimethyl-4-methylthiobromobenzene, magnesium and tetrahydrofuran, refluxes it for Grignard carboxylation, and then introduces carbon dioxide for Grignardization to obtain 2,3-methyl-4-methylthiobenzoic acid.

[0062] In this invention, the magnesium is preferably magnesium strip.

[0063] In this invention, the molar ratio of 2,3-dimethyl-4-methylthiobromobenzene to magnesium is preferably 1:(1-1.5), more preferably 1:(1.1-1.4), and most preferably 1:(1.2-1.3). In this invention, the mass ratio of 2,3-dimethyl-4-methylthiobromobenzene to tetrahydrofuran is preferably 1:(4-10), more preferably 1:(4-6), and most preferably 1:4.

[0064] The present invention does not impose any special limitations on the mixing process; any process known to those skilled in the art can be used.

[0065] In this invention, the preferred time for the carboxylation reaction is 2-3 h, more preferably 2.2-2.8 h, and most preferably 2.4-2.6 h.

[0066] In this invention, the carboxylation reaction is completed under the condition that the content of 2,3-dimethyl-4-methylthiobromobenzene is ≤1%.

[0067] After the carboxylation reaction is completed, the present invention preferably includes cooling to 0°C. The present invention does not have any special limitations on the cooling process, and any process known to those skilled in the art can be used.

[0068] In this invention, the molar ratio of 2,3-dimethyl-4-methylthiobromobenzene to carbon dioxide is preferably 1:(3-4), more preferably 1:(3.2-3.8), and most preferably 1:(3.4-3.6). The temperature at which the carbon dioxide is added is preferably 0-5°C, more preferably 1-4°C, and most preferably 2-3°C.

[0069] In this invention, the temperature of the Grignardization reaction is preferably 0-5°C, more preferably 1-4°C, and most preferably 2-3°C; the time of the Grignardization reaction is preferably 0.5-5h, more preferably 1-3h, and most preferably 3h.

[0070] 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 THF under reduced pressure, adding water and stirring for 1 hour, filtering and drying.

[0071] 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 a first oxidation reaction to obtain 2,3-dimethyl-4-methanesulfonylbenzoic acid.

[0072] 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.

[0073] 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.

[0074] In this invention, the molar ratio of 2,3-methyl-4-methylthiobenzoic acid to hydrogen peroxide is preferably 1:(2.5-3.5), more preferably 1:(2.8-3.2).

[0075] In this invention, the hydrogen peroxide is preferably added dropwise, and the temperature of the dropwise addition is preferably 30-50°C, more preferably 30°C. This invention does not impose any special limitations on the dropwise addition process; any process well-known to those skilled in the art can be used.

[0076] In this invention, the temperature of the first oxidation reaction is preferably 30-50°C, more preferably 30°C; the time is preferably 4-6 hours, more preferably 4.5-5.5 hours, and most preferably 5 hours.

[0077] In this invention, the first oxidation reaction is completed under the condition that the content of 2,3-methyl-4-methylthiobenzoic acid is ≤1%.

[0078] After the first oxidation reaction is completed, the present invention preferably includes cooling the obtained product system to 25°C, stirring for 2 hours, filtering, washing with water and drying.

[0079] 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.

[0080] In this invention, the mass ratio of 2,3-dimethyl-4-methanesulfonylbenzoic acid to methanol is preferably 1:(3-4), more preferably 1:(3.2-3.8), and most preferably 1:(3.4-3.6).

[0081] 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.

[0082] In this invention, the thionyl chloride is preferably added by dropwise addition, which is preferably carried out under reflux conditions. 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.

[0083] In this invention, the molar ratio of 2,3-dimethyl-4-methanesulfonylbenzoic acid to thionyl chloride is preferably 1:(1.5-2), more preferably 1:(1.6-1.8).

[0084] In this invention, the esterification reaction is preferably carried out under reflux conditions, and the esterification reaction time is preferably 0.5 to 8 hours, more preferably 1 to 4 hours, and most preferably 2 hours.

[0085] The esterification reaction is preferably completed under the condition that the content of 2,3-dimethyl-4-methanesulfonylbenzoic acid is ≤1%.

[0086] After the esterification reaction is completed, the present invention preferably further includes cooling the obtained product system to room temperature and removing methanol under reduced pressure.

[0087] After obtaining methyl 2,3-dimethyl-4-methanesulfonylbenzoate, the present invention mixes the methyl 2,3-dimethyl-4-methanesulfonylbenzoate, carbon tetrachloride, benzoyl peroxide and N-bromosuccinimide, and then refluxes the mixture to carry out a second bromination reaction to obtain methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate.

[0088] In this invention, the volume ratio of methyl 2,3-dimethyl-4-methanesulfonylbenzoate to carbon tetrachloride is preferably 5:1; the mass ratio of methyl 2,3-dimethyl-4-methanesulfonylbenzoate to benzoyl peroxide is preferably 1:(0.1-1.0), more preferably 1:(0.1-0.5); the molar ratio of methyl 2,3-dimethyl-4-methanesulfonylbenzoate to N-bromosuccinimide is preferably 1:(1.1-1.5), more preferably 1:(1.2-1.4), and most preferably 1:1.3.

[0089] 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.

[0090] In this invention, the second bromination reaction is preferably carried out under reflux conditions, wherein the reflux temperature is preferably 65-80°C, more preferably 70-75°C, and the time is preferably 3-5 h, more preferably 3.5-4.5 h.

[0091] The second bromination reaction is preferably completed under the condition that the content of methyl 2,3-dimethyl-4-methanesulfonylbenzoate is ≤1% as determined by HPLC sampling.

[0092] After the second bromination reaction is completed, the present invention preferably includes cooling the obtained product system to room temperature, adding saturated sulfurous acid for quenching, allowing it to stand to separate the oil layer, washing the obtained oil layer with water three times, and concentrating it.

[0093] After obtaining methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate, the present invention mixes the methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate with acetonitrile, cools the mixture, adds N-methylmorpholine oxide, and carries out a second oxidation reaction to obtain methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate.

[0094] In this invention, the molar ratio of N-methylmorpholine oxide and methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate is preferably (1.5-2.5):1, more preferably (1.8-2.2):1; the mass ratio of acetonitrile and methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate is preferably 5:1.

[0095] 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.

[0096] In this invention, the target temperature for cooling is preferably 0°C.

[0097] In this invention, the N-methylmorpholine oxide is preferably added in batches, and the number of batches added is preferably 1 to 20 times, more preferably 5 to 15 times, and most preferably 10 times.

[0098] In this invention, the temperature of the second oxidation reaction is preferably 0-10°C, more preferably 2-8°C, and most preferably 4-6°C; the time is preferably 2-4 hours.

[0099] The second oxidation is preferably completed under the condition that the content of Top-4 is ≤1% according to HPLC sampling test.

[0100] After the second oxidation reaction is completed, the present invention preferably further includes adding water to dissolve the obtained product system, adding dichloromethane for extraction, washing with water, separating the oil layer for concentration.

[0101] After obtaining methyl 3-formyl-2-methyl-4-methylsulfonyl benzoate, the present invention mixes the methyl 3-formyl-2-methyl-4-methylsulfonyl benzoate, hydroxylamine hydrochloride and ethanol, and refluxes them for oxime reaction to obtain methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate.

[0102] In this invention, the molar ratio of methyl 3-formyl-2-methyl-4-methylsulfonyl benzoate to hydroxylamine hydrochloride is preferably 1:(1.1-1.5), more preferably 1:(1.2-1.4), and most preferably 1:1.3; the mass ratio of methyl 3-formyl-2-methyl-4-methylsulfonyl benzoate to ethanol is preferably 1:(3-5), more preferably 1:(3.5-4.5), and most preferably 1:(3.8-4.2).

[0103] 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.

[0104] In this invention, the temperature of the oxime reaction is preferably 30-100°C, more preferably 60-90°C, and most preferably 80°C; the time is preferably 2-4 h, more preferably 2.5-3.5 h, and most preferably 2.8-3.2 h.

[0105] The oxime reaction is preferably completed under the condition that the content of Top-5 in HPLC sampling test is ≤1%.

[0106] After the oxime reaction is completed, the present invention preferably includes cooling the obtained product system to room temperature, concentrating and recovering ethanol, adding water to dissolve, adding dichloromethane to extract three times, washing with water twice to combine the oil layers, and concentrating.

[0107] After obtaining the methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methanesulfonyl)benzoate, the present invention mixes the methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methanesulfonyl)benzoate with dichloromethane, adds N-chlorosuccinimide for chlorination, adds triethylamine, and sequentially purges nitrogen and ethylene for dipolar addition reaction to obtain the methyl 3-(4,5-dihydro-3-isooxazolyl)-2-methyl-4-methylsulfonylbenzoate.

[0108] In this invention, the molar ratio of methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate to N-chlorosuccinimide is preferably 1:(1.1-1.5), more preferably 1:(1.2-1.4); the mass ratio of methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate to dichloromethane is preferably 1:(3-5), more preferably 1:(3.5-4.5).

[0109] 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.

[0110] In this invention, the N-chlorosuccinimide is preferably added in batches, and the number of batch additions is preferably 1 to 30 times, more preferably 10 to 20 times. In this invention, the temperature for the batch addition is preferably 20 to 30°C, more preferably 22 to 28°C, and most preferably 24 to 26°C.

[0111] In this invention, the temperature of the chlorination reaction is preferably 20-30°C, more preferably 22-28°C, and most preferably 24-26°C; the time is preferably 1-3 hours, more preferably 2 hours.

[0112] The chlorination reaction is preferably completed under the condition that the content of Top-6 is ≤1% according to HPLC sampling test.

[0113] After the chlorination reaction is completed, the present invention preferably includes transferring the obtained product system into a high-pressure reactor, adding triethylamine, purging with nitrogen three times, maintaining pressure at 1.0 MPa for 30 min, releasing nitrogen, purging with ethylene three times, introducing pressure at 1 MPa, starting stirring, raising the temperature to 60°C, reacting for 2-3 h, washing the obtained reaction solution with water three times, separating the oil layer, concentrating and purifying.

[0114] The preparation method of methyl 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate 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.

[0115] Example 1

[0116] Preparation of 2,3-dimethyl-4-methylthiobenzene (Top-B):

[0117] 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 mixed. Under stirring, 243.29 g of butyl nitrite (2.24 mol, 1.1 eq) was added dropwise (the temperature was controlled at 30°C during the dropwise addition). After the dropwise addition was completed within 3 hours, the mixture was kept at this temperature for 30 minutes. GC samples were taken for analysis. When the raw material content was ≤1%, the reaction was stopped, and the solution was directly removed under reduced pressure using a water pump to recover dimethyl disulfide and butyl nitrite. After the solution removal was completed, the mixture was distilled using an oil pump to obtain 309.7 g of 2,3-dimethyl-4-methylthiobenzene (Top-B) with a content of 95.0% and a yield of 95%. 1 HNMR: δ2.32(3H),2.33(3H),2.50(3H),7.43(1H),7.45(1H),7.21(1H);

[0118] Preparation of 2,3-dimethyl-4-methylthiobromobenzene (Top-C):

[0119] 700g of 2,3-dimethyl-4-methylthiobenzene (4.48mol, 1eq) and 2800g of dichloromethane were mixed, and 868.8g of liquid bromine (5.58mol, 1.2eq) was added dropwise under stirring. The reaction temperature was controlled at 3℃. After the addition was completed, the mixture was kept at this temperature for 1h. The sample was taken and analyzed by high performance liquid chromatography until the Top-B content was <1%, indicating the end of the reaction. 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 1033.01g of 2,3-dimethyl-4-methylthiobromobenzene (Top-C), with a content of 97.6% and a yield of 97.7%. 1 HNMR: δ2.43(3H),2.33(3H),2.50(3H),7.76(1H),7.79(1H);

[0120] Preparation of 2,3-methyl-4-methylthiobenzoic acid (Top-1):

[0121] 10.6 g Mg (0.44 mol, 2.0 eq), 300 g tetrahydrofuran (THF), and 50 g of the 2,3-dimethyl-4-methylthiobromobenzene were stirred evenly and purged with nitrogen three times. The mixture was heated to reflux under nitrogen protection and kept under reflux for 5 h. TLC analysis was performed. After the starting material spotting time, the temperature was lowered to 0 °C, and CO2 was bubbled through. TLC sampling was used to track the reaction. After the starting material spotting time 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 55.83 g of solid material, which was dried at 70 °C for 6 h to obtain 44.67 g of 2,3-methyl-4-methylthiobenzoic acid with a purity of 94.6% and a yield of 98.0%. 1 HNMR: δ2.43(3H),2.33(3H),3.22(3H),7.76(1H),7.79(1H);

[0122] Preparation of 2,3-dimethyl-4-methanesulfonylbenzoic acid (Top-2):

[0123] 100g of the 2,3-methyl-4-methylthiobenzoic acid (0.48mol, 1eq) and 500g of acetic acid were stirred evenly, heated to 30℃, and 154.8g of hydrogen peroxide (1.44mol, 3.0eq) was slowly added dropwise, controlling the temperature within the range of 45℃. After the addition was completed, the reaction was kept at this temperature for 5h until the Top-1 content was ≤1% until the reaction was completed. The temperature was then lowered to 25℃ and stirred for 2h. The mixture was then filtered and washed with water to obtain 131.4g of wet product. After drying, 107.76g of 2,3-dimethyl-4-methanesulfonylbenzoic acid (Top-2) was obtained, with a content of 97.9% and a yield of 96.4%. 1HNMR: δ2.35(3H),2.33(3H),3.22(3H),7.76(1H),7.51(1H),11.20(1H);

[0124] Preparation of methyl 2,3-dimethyl-4-methanesulfonylbenzoate (Top-3):

[0125] 100g of 2,3-dimethyl-4-methanesulfonylbenzoic acid (0.429mol, 1eq) and 500g of methanol were stirred evenly, heated to reflux, and 117.7g of thionyl chloride (0.98mol, 2.0eq) was slowly added dropwise over 1-2 hours. The reaction was maintained at this temperature for 6 hours until the Top-2 content was ≤1%. The mixture was then cooled to room temperature, and methanol was removed under reduced pressure to obtain 105.9g of methyl 2,3-dimethyl-4-methanesulfonylbenzoate (Top-3) with a purity of 96.6% and a yield of 98.4%. 1 H NMR: δ3.72(3H),2.35(3H),2.33(3H),3.22(3H),7.76(1H),7.51(1H);

[0126] Preparation of methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate (Top-4):

[0127] 50 g Top-3 (0.20 mol, 1 eq), 250 g carbon tetrachloride, 5 g benzoyl peroxide (BPO) (m / m, 1%), and 40 g N-bromosuccinimide (NBS) (0.30 mol, 1.5 eq) were stirred until homogeneous, heated to reflux, and the temperature was controlled at 85 °C during reflux. The reaction was carried out for 2 h, and HPLC samples were taken for analysis until the Top-3 content was ≤1%. The reaction was then stopped, cooled to room temperature, and 50 g saturated sulfurous acid was added to quench the reaction. The mixture was allowed to stand and the oil layer was separated. The oil layer was washed three times with water (30 mL each time), and concentrated to obtain 57.06 g Top-4 with a content of 90.0% and a yield of 80.0%. 1H NMR: δ 3.72 (3H), 2.35 (3H), 3.22 (3H), 4.49 (2H), 7.76 (1H), 7.51 (1H).

[0128] Preparation of methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate (Top-5):

[0129] 100g Top-4 (0.286mol, 1eq) and 500g acetonitrile were stirred evenly and cooled to 0℃. 50.19g N-methylmorpholine oxide (0.429mol, 1.5eq) was added in 10 batches, and the temperature was controlled at 0℃. The reaction was maintained for 2h. HPLC sampling and analysis were performed until the content of Top-4 was ≤1%. Acetonitrile was recovered by concentration, dissolved in 100mL of water, extracted three times with dichloromethane (100mL / time), and washed twice with water (50mL / time). The oil layer was separated and concentrated to obtain 70.55g Top-5 with a content of 93.4% and a yield of 90%. 1H NMR: δ 3.72 (3H), 2.35 (3H), 3.22 (3H), 7.76 (1H), 7.51 (1H), 10.05 (1H).

[0130] Preparation of methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate (Top-6):

[0131] 60.6 g of Top-5 (0.22 mol, 1 eq), hydroxylamine hydrochloride (0.264 mol, 1.2 eq), and 303 g of ethanol were stirred until homogeneous. The mixture was heated to reflux and the reflux temperature was controlled at 80 °C. The reaction was maintained at this temperature for 3 h. HPLC analysis was performed until the content of Top-5 was ≤1%, which was considered the endpoint of the reaction. The mixture was cooled to room temperature, concentrated, and the ethanol was recovered. 50 mL of water was added to dissolve the mixture, and dichloromethane was added for extraction three times (60 mL / time). The mixture was washed twice with water (30 mL / time). The oil layers were combined and concentrated to obtain 58.81 g of compound Top-6, with a purity of 96.5% and a yield of 95.2%. 1H NMR: δ 3.72 (3H), 2.35 (3H), 3.22 (3H), 7.76 (1H), 7.51 (1H), 8.18 (1H), 4.00 (1H).

[0132] Preparation of methyl 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate (Top-7):

[0133] 100g of Top-6 (0.356mol, 1eq) and 500g of dichloromethane were stirred until homogeneous. 56.8g of N-chlorosuccinimide (NCS, 0.427mol, 1.2eq) was added in batches at 30℃ and the reaction was maintained at this temperature for 2 hours. Samples were taken for analysis, and HPLC testing was performed until the Top-6 content was ≤1%. The mixture was then transferred to a high-pressure reactor, and triethylamine (0.284mol, 0.8eq) was added. The reactor was purged with nitrogen three times, and the pressure was maintained at 1.0 MPa for 30 minutes. After releasing the nitrogen, ethylene was introduced to purge the mixture three times, and a pressure of 1 MPa was introduced. Stirring was started, and the temperature was raised to 60℃. The reaction was allowed to proceed for 2-3 hours. HPLC analysis showed that methyl 3-[(hydroxyimino)chloromethyl]-2-methyl-4-(methanesulfonyl)benzoate was ≤1%. The reaction was stopped, and the reaction solution was washed three times with water (100mL each time). The oil layer was separated, concentrated, and 106.19g of the compound was obtained. Top-7 crude product, purity 91.6%; 106.1g of the crude product was added to a reaction flask with 318g of ethanol and stirred. The mixture was heated to reflux until the system was completely dissolved. The mixture was then slowly cooled to room temperature, filtered, and dried to obtain 93.3g of Top-7 product, purity 99.0%. 1H NMR: δ 3.72 (3H), 2.35 (3H), 3.22 (3H), 4.38 (2H), 3.29 (2H), 7.76 (1H), 7.51 (1H).

[0134] 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 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-methylsulfonylbenzoate, characterized in that, Includes the following steps: Copper powder, dimethyl disulfide and 3-amino-o-xylene were mixed and then nitrite was added to carry out a diazotization reaction to obtain 2,3-dimethyl-methylthiobenzene. The 2,3-dimethyl-4-methylthiobenzene and dichloromethane were mixed and then liquid bromine was added to carry out the first bromination reaction to obtain 2,3-dimethyl-4-methylthiobromobenzene; The 2,3-dimethyl-4-methylthiobromobenzene, magnesium and tetrahydrofuran were mixed and refluxed for Grignard carboxylation. Then carbon dioxide was introduced for Grignardization to obtain 2,3-dimethyl-4-methylthiobenzoic acid. The 2,3-dimethyl-4-methylthiobenzoic acid and acetic acid were mixed, and then hydrogen peroxide was added to carry out the first oxidation reaction to obtain 2,3-dimethyl-4-methanesulfonylbenzoic acid; the molar ratio of the 2,3-dimethyl-4-methylthiobenzoic acid and hydrogen peroxide in the hydrogen peroxide was 1:

3. 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. The methyl 2,3-dimethyl-4-methanesulfonylbenzoate, carbon tetrachloride, benzoyl peroxide and N-bromosuccinimide were mixed and refluxed to carry out a second bromination reaction to obtain methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate. The methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate was mixed with acetonitrile, cooled, and then N-methylmorpholine oxide was added to carry out a second oxidation reaction to obtain methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate; the N-methylmorpholine oxide was added in batches, and the number of batches was 10; the temperature of the second oxidation reaction was 0~10℃, and the time was 2~4h; The methyl 3-formyl-2-methyl-4-methylsulfonyl benzoate, hydroxylamine hydrochloride, and ethanol were mixed and refluxed to undergo an oxime reaction to obtain methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate; The methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methanesulfonyl)benzoate was mixed with dichloromethane, and then N-chlorosuccinimide was added for chlorination. Triethylamine was added, and nitrogen gas and ethylene were successively introduced for displacement and dipole addition reaction to obtain the methyl 3-(4,5-dihydro-3-isooxazolyl)-2-methyl-4-methylsulfonylbenzoate.

2. The preparation method according to claim 1, characterized in that, The molar ratio of copper powder to 3-amino-o-xylene is (0.6~0.7):1; The molar ratio of n-butyl nitrite to 3-aminoo-xylene is 1.1:1; The molar ratio of dimethyl disulfide to 3-aminoo-xylene is (1.0~2.0):

1.

3. The preparation method according to claim 1 or 2, characterized in that, The diazotization reaction is carried out at a temperature of 30-35°C for 3-5 hours.

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

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

6. The preparation method according to claim 1, characterized in that, The molar ratio of 2,3-dimethyl-4-methylthiobenzoic acid to hydrogen peroxide is 1:(2.5~3.5).

7. The preparation method according to claim 1, characterized in that, The molar ratio of methyl 2,3-dimethyl-4-methanesulfonylbenzoate to N-bromosuccinimide is 1:(1.1~1.5). The mass ratio of methyl 2,3-dimethyl-4-methanesulfonylbenzoate to benzoyl peroxide is 1:(0.1~1.0). The volume ratio of methyl 2,3-dimethyl-4-methanesulfonylbenzoate to carbon tetrachloride is 5:

1.

8. The preparation method according to claim 1, characterized in that, The molar ratio of N-methylmorpholine oxide to methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate is (1.5~2.5):1; The mass ratio of acetonitrile to methyl 4-methanesulfonyl-3-bromomethyl-2-methylbenzoate is 5:

1.

9. The preparation method according to claim 1, characterized in that, The molar ratio of methyl 3-formyl-2-methyl-4-methylsulfonyl benzoate to hydroxylamine hydrochloride is 1:(1.1~1.5). The mass ratio of methyl 3-formyl-2-methyl-4-methylsulfonylbenzoate to ethanol is 1:(3~5).

10. The preparation method according to claim 1, characterized in that, The molar ratio of methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate to N-chlorosuccinimide is 1:(1.1~1.5). The mass ratio of methyl 3-[(hydroxyimino)methyl]-2-methyl-4-(methylsulfonyl)benzoate to dichloromethane is 1:(3~5).