CN111848536A - Preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole - Google Patents
Preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole Download PDFInfo
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Abstract
The invention belongs to the field of chemical synthesis, and relates to a preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole, which is obtained by taking 2, 3-dimethylaniline as a starting material to react, and obtaining an oximation product by diazotizing, brominating and then oximating the 2, 3-dimethylaniline. The invention has the advantages that the two latter routes break the monopoly of the traditional route, are safe and environment-friendly, are easy to industrialize and have market prospect.
Description
Technical Field
The invention relates to the field of chemical synthesis, and particularly provides a preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole.
Background
The topramezone is a novel herbicide developed by Pasteur Germany, has a remarkable effect on preventing and removing weeds resistant to glyphosate, triazines, acetolactate synthase inhibitors and acetyl coenzyme A carboxylase inhibitors, has a good preventing and removing effect, belongs to a broad-spectrum post-emergence herbicide, and can effectively prevent and remove annual gramineae and broadleaf weeds in corn fields.
3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole is the most important intermediate in the synthesis of topramezone, and the synthetic routes are mainly two of the following (see patent US 2003/0216580 a 1):
(1) 2, 3-dimethylaniline is used as an initial raw material to react to obtain an intermediate 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole (E), and the reaction route is as follows:
(2) 3-nitro-o-xylene is used as an initial raw material to react to obtain an intermediate 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole (E), and the reaction route is as follows:
the two routes for synthesizing the intermediate (E) have more steps, hydrogen, ethylene and chlorine are used for reaction, flammable and explosive toxic gases are generated, the safety coefficient is low, the operation is complex, and the requirement of safe production is difficult to meet, so that a production method which is safer and more environment-friendly and easy to industrialize is urgently needed to fill the blank in the field.
Disclosure of Invention
The invention provides a preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole aiming at the blank of the technology, which is obtained by taking 2, 3-dimethylaniline as a starting material to react, and obtaining an oximation product by diazotizing, brominating and then oximating the 2, 3-dimethylaniline. The invention has the advantages that the two latter routes break the monopoly of the traditional route, are safe and environment-friendly, are easy to industrialize and have market prospect.
Aiming at the related problems in the prior art, the inventor provides a reaction route of a novel intermediate 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole for simplifying steps and improving safety index, the reaction route adopts the same raw materials as the route (1), but the process is simpler, the oxime oxidation and thioether oxidation are carried out by a one-pot method to form sulfone, a water-soluble oxidant is used for replacing chlorine, and the isoxazole is cyclized by using vinyl acetate to replace ethylene, so that the method has obvious advantages in the aspects of safety, environmental protection, cost control and process control, and has great market potential and popularization prospect.
The specific technical scheme of the invention is as follows:
a preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole (E) comprises the preparation of a compound B, and comprises the following specific steps:
(1) respectively weighing 2, 3-dimethylaniline, dimethyl disulfide and copper powder in a round-bottom flask at normal temperature, placing the flask in a water bath, heating to 30 ℃, dropwise adding n-butyl nitrite, reacting for 3 hours, and finishing the reaction; filtering the copper powder, distilling the filtrate to recover the solvent, and collecting the fraction above 120 ℃ to obtain a compound A;
(2) adding the compound A and dichloroethane into a reaction bottle, dropwise adding bromine at 25-30 ℃, reacting for 0.5h, adjusting the pH value to 2-3 after the reaction is finished, washing with water at room temperature, drying an organic phase with anhydrous sodium sulfate, and distilling to recover a solvent to obtain a compound B;
The above two steps are the same as the prior art, and those skilled in the art can refer to the related technical solution described in patent US 2003/0216580 a1, which is not described herein again by the inventor; after obtaining the above compound B, the inventors further disclose the following reaction steps:
(3) adding DMSO, THF and potassium tert-butoxide into a reaction flask, and cooling to-15 ℃; slowly dropwise adding a mixed feed liquid of the compound B, n-butyl nitrite and THF, dropwise adding for 2h, carrying out heat preservation reaction for 3-4h, after the reaction is finished, dropwise adding acid for quenching, wherein the acid dosage is 1.05 times of the molar weight of potassium tert-butoxide, controlling the temperature below-5 ℃ in the acid dropwise adding process, dropwise adding for about 1h, after the dropwise adding is finished, carrying out heat preservation and stirring for 0.5h at the temperature, after the heat preservation is finished, heating the feed liquid, distilling and recovering the solvent, carrying out water washing extraction, and distilling and recovering the solvent by an organic phase to obtain a compound C;
(4) adding a reaction solvent, a compound C and a catalyst sodium tungstate into a reaction bottle, heating to a reaction temperature of 80-90 ℃, dropwise adding an oxidant, carrying out heat preservation reaction for 5-6h, cooling to-5 ℃ after the reaction is finished, and carrying out suction filtration to obtain a compound D; the purity of the compound D obtained by detection reaches more than 95 percent;
(5) adding a reaction solvent, a compound D, vinyl acetate and sodium carbonate into a reaction bottle, heating to a reaction temperature of 75-85 ℃, reacting for 3-4h, after the reaction is finished, washing a reaction product twice with 15% dilute hydrochloric acid, then separating liquid to obtain an organic phase, washing the obtained organic phase once with water, drying with anhydrous sodium sulfate, and removing the solvent by rotary evaporation to obtain a compound 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole E.
Wherein the application is characterized by steps (3) to (5), and the synthetic route is as follows:
(3) the bromide compound B reacts under the action of an oximation agent to generate an oximation compound C
(4) The oxime compound C reacts under the action of an oxidant to generate an oxime oxygen product compound D:
(5) the oxime oxygen product compound D is subjected to cyclization reaction under the action of vinyl acetate to generate 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole (E);
the reaction formula of the overall reaction of the present application is thus as follows:
the specific process in the above steps 3-5 has the following technical features:
the reaction solvent in the step (3) is a mixed solution of DMSO and THF, the dosage of DMSO is 1-1.1 times of the weight of the compound B, and the dosage of THF is 4.7-5 times of the weight of the compound B.
The dosage of the potassium tert-butoxide in the step (3) is 3.5 times of the molar weight of the compound B;
the acid in the step (3) is hydrochloric acid;
the dosage of the n-butyl nitrite in the step (3) is 1.5 times of the molar weight of the compound B;
the reaction solvent in the step (4) is one of ethanol, DMSO and DMF; the dosage of the reaction solvent is 1.1 to 1.5 times of the mass of the compound C;
the dosage of the catalyst sodium tungstate in the step (4) is 0.1 to 0.15 times of the molar weight of the compound C;
The oxidant in the step (4) is sodium hypochlorite; the addition amount of the oxidant is 2 to 2.25 times of the molar amount of the compound C;
the reaction solvent in the step (5) is one of dichloroethane, toluene and acetonitrile; the dosage of the reaction solvent is 2-2.3 times of the mass of the compound D;
the dosage of the vinyl acetate in the step (5) is 1.08-1.15 times of the mass of the compound D;
the amount of the sodium carbonate used in the step (5) is 1.05 to 1.15 times of the mass of the compound D.
The oximation product is oxidized by a one-pot method, and then the target product is obtained by ring formation of isoxazole, which is completely different from the path in the prior art, 3-methyl-4-bromobenzene sulfide-2-oxime is firstly oxidized to obtain 3-methyl-4-bromobenzene sulfone-2-oxime, and then chlorinated to obtain 3-methyl-4-bromobenzene sulfone-2-chlorooxime, two-step reaction is needed to obtain a compound D (3-methyl-4-bromobenzene sulfone-2-chlorooxime), the two-step reaction is a dangerous chemical process with key supervision, hydrogen peroxide is used in the oxidation reaction, the reaction speed is high, the heat release is obvious, the risk of violent temperature rise is easily accumulated, the storage requirement condition is high, oxygen is easily generated by decomposition, and the explosion risk is generated; the chlorination reaction uses a highly toxic chemical chlorine gas, the storage pressure of the chlorine gas is high, and once the chlorine gas leaks, the danger is high; the chlorination reaction has obvious heat release, violent reaction, high speed and large heat release; impurities in the chlorine, such as oxygen, nitrogen trichloride and the like, are easy to generate danger in the using process, and especially after the nitrogen trichloride is accumulated, explosion danger is easy to generate; this is also a problem that is difficult to solve by the prior art;
The process is a one-step reaction, the 3-methyl-4-bromobenzene methyl sulfide-2-oxime directly reacts under the action of a water-soluble oxidant sodium hypochlorite to obtain the compound D, the reaction condition is mild, the reaction speed is controllable, the operation is easy, the use of hydrogen peroxide and highly toxic chlorine is avoided, the process is simplified, the reaction flow is shortened, the types of raw materials are reduced, the safety index in the material storage and reaction operation processes is improved, and the cost is reduced.
In addition, in the prior art, an ethylene pressurization process is adopted, the reaction condition is strict, the temperature is 65 ℃, the pressure is 2.0MPa, ethylene is extremely flammable, the ethylene is mixed with air to form an explosive mixture, and the ethylene is in contact with open fire, high heat or an oxidant, so that the danger of combustion and explosion is caused, and the ethylene has a strong anesthetic effect;
the process adopts vinyl acetate to replace ethylene, the raw materials are common and easy to obtain, the toxicity is low, the reaction is carried out under normal pressure, the temperature is reduced to 75 ℃, the condition is mild, and the risk is reduced.
After the final yield and the purity of the product are evaluated, the purity of the product obtained by the process is equivalent to that in the prior art, the yield is slightly higher by 2-3%, and the process is safer and more environment-friendly.
In conclusion, the process can be directly matched with the prior art for use, but the process is simpler, the oxime oxidation and the thioether oxidation are carried out by a one-pot method to form the sulfone, the chlorine is replaced by the water-soluble oxidant, the ethylene is replaced by the vinyl acetate in the ring formation of the isoxazole, the process has obvious advantages in the aspects of safety, environmental protection, cost control and process control, and has great market potential and popularization prospect.
Detailed Description
The present invention will be described in further detail with reference to the following examples, but it should not be construed that the scope of the above subject matter is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention, and the following embodiments are all completed by adopting the conventional prior art except for the specific description.
Compound B was obtained by the preparation of step 1-2 described in the related art scheme described in patent US 2003/0216580 a1, and the following examples are all described with compound B as the starting reactant;
example 1
A preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole comprises the following specific steps:
(1) synthesis of Compound C
To the reaction flask were added 33.33g of DMSO, 153.35g of THF and 53.19g of potassium tert-butoxide, and the temperature was lowered to-15 ℃. Slowly adding a mixed material liquid of 31.67g (0.133mol) of the compound B, 20.96g of n-butyl nitrite, 30.0g of DMSO and 100g of THF dropwise, adding dropwise for 2 hours, reacting for 3-4 hours under heat preservation, adding hydrochloric acid dropwise after the reaction is finished, controlling the temperature to be below-5 ℃, distilling the material liquid to recover the solvent, extracting by washing with water, distilling the organic phase to recover the solvent, and obtaining 27.37g of the compound C with the yield of 75.2%.
(2) Synthesis of Compound D
Adding 30.11g of ethanol, 27.37g (0.1mol) of compound C and 0.33g (0.001mol) of sodium tungstate into a reaction bottle, heating to 80 ℃, dropwise adding 113.85g (0.2mol) of sodium hypochlorite, preserving heat for reaction for 5.5h, cooling to-5 ℃ after the reaction is finished, carrying out suction filtration, and drying at 50 ℃ to obtain 27.48g of compound D with the yield of 81.9%.
(3) Synthesis of Compound E
Adding 54.96g of dichloroethane, 27.48g (0.0819mol) of the compound D, 7.95g (0.0885mol) of vinyl acetate and 9.61g (0.0860mol) of sodium carbonate into a reaction bottle, heating to 75 ℃, reacting for 3.2 hours, adding 30.0g of 15% diluted hydrochloric acid to perform acid cleaning twice at the temperature of 25-30 ℃ after the reaction is finished, performing 15-20min each time, standing and separating to obtain an organic phase, washing once with 30.0g of industrial water, and standing and separating again to obtain an organic phase; the organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give compound E21.69 g, 81.2% yield, 50.01% overall yield over three steps. The overall process yield from the original feedstock to the final product compound E was 40.38%.
Example 2
A preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole comprises the following specific steps:
(1) synthesis of Compound C
DMSO 32.83g, THF 151.34g, and potassium tert-butoxide 52.77g were added to the reaction flask and the temperature was reduced to-15 ℃. Slowly adding 31.41g (0.1313mol) of compound B, 20.80g of n-butyl nitrite, 30.0g of DMSO and 100. 100g of THF in a dropwise manner, reacting for 3-4h under heat preservation, adding hydrochloric acid in a dropwise manner after the reaction is finished, controlling the temperature below-5 ℃, distilling the material liquid to recover the solvent, extracting with water, distilling the organic phase to recover the solvent, and obtaining 27.37g of compound C with the yield of 75.8%.
(2) Synthesis of Compound D
Adding 41.05g of DMSO, 27.37g (0.1mol) of compound C and 0.495g (0.0015mol) of sodium tungstate into a reaction bottle, heating to 90 ℃, dropwise adding 128.08g (0.225mol) of sodium hypochlorite, preserving heat for 5.0h, cooling to-5 ℃ after the reaction is finished, performing suction filtration, and drying at 50 ℃ to obtain 27.62g of compound D, wherein the yield is 82.3%;
(3) synthesis of Compound E
Adding 63.52g of toluene, 27.62g (0.0823mol) of compound D, 8.15g (0.0946mol) of vinyl acetate and 10.13g (0.0946mol) of sodium carbonate into a reaction bottle, heating to 85 ℃, reacting for 3.0h, adding 30.0g of 15% dilute hydrochloric acid to wash twice at the temperature of 25-30 ℃ after the reaction is finished, washing for 15-20min each time, standing and separating to obtain an organic phase, washing once with 30.0g of industrial water, standing and separating again to obtain an organic phase; the organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give compound E21.33 g in 78.9% yield, 49.22% overall yield over the three steps. The overall process yield from the original feedstock to the final product compound E was 39.75%.
Example 3
A preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole comprises the following specific steps:
(1) synthesis of Compound C
To a reaction flask were added 33.25g of DMSO, 153.0g of THF and 53.12g of potassium tert-butoxide, and the temperature was lowered to-15 ℃. Slowly adding a mixed material liquid of 31.62g (0.1328mol) of the compound B, 20.94g of n-butyl nitrite, 30.0g of DMSO and THF100g dropwise, adding dropwise for 2 hours, reacting for 3-4 hours under heat preservation, adding hydrochloric acid dropwise after the reaction is finished, controlling the temperature to be below-5 ℃, distilling the material liquid to recover the solvent, extracting by washing with water, distilling the organic phase to recover the solvent, and obtaining 27.37g of the compound C with the yield of 75.3%.
(2) Synthesis of Compound D
Adding 35.58g of DMF, 27.37g (0.1mol) of compound C and 0.413g (0.00125mol) of sodium tungstate into a reaction bottle, heating to 85 ℃, dropwise adding 119.54g (0.21mol) of sodium hypochlorite, keeping the temperature for reaction for 6 hours, cooling to-5 ℃ after the reaction is finished, carrying out suction filtration, and drying at 50 ℃ to obtain 25.57g of compound D, wherein the yield is 76.2%;
(3) synthesis of Compound E
Adding 48.5g of acetonitrile, 25.57g (0.0762mol) of compound D, 7.35g (0.0853mol) of vinyl acetate and 8.97g (0.0838mol) of sodium carbonate into a reaction bottle, heating to 80 ℃, reacting for 4 hours, adding 30.0g of 15% diluted hydrochloric acid to perform acid cleaning twice at the temperature of 25-30 ℃ after the reaction is finished, performing 15-20min each time, standing and separating to obtain an organic phase, washing once with 30.0g of industrial water, and standing and separating again to obtain an organic phase; the organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give the compound e19.15g, 75.8% yield, 43.49% overall yield over the three steps. The overall process yield from the original feedstock to the final product compound E was 35.12%.
Example 4
A preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole comprises the following specific steps:
(1) synthesis of Compound C
DMSO 32.76g, THF 151.0g and potassium tert-butoxide 52.7g were added to the reaction flask and the temperature was reduced to-15 ℃. Slowly adding a mixed material liquid of 31.38g (0.1318mol) of the compound B, 20.77g of n-butyl nitrite, 30.0g of DMSO and THF100g dropwise, adding dropwise for 2 hours, reacting for 3-4 hours under heat preservation, adding hydrochloric acid dropwise after the reaction is finished, controlling the temperature to be below-5 ℃, distilling the material liquid to recover the solvent, extracting by washing with water, distilling an organic phase to recover the solvent, and obtaining 27.37g of the compound C with the yield of 75.9%.
(2) Synthesis of Compound D
Adding 41.05g of ethanol, 27.37g (0.1mol) of compound C and 0.495g (0.0015mol) of sodium tungstate into a reaction bottle, heating to 88 ℃, dropwise adding 125.23g (0.22mol) of sodium hypochlorite, preserving heat for reaction for 5.0h, cooling to-5 ℃ after the reaction is finished, carrying out suction filtration, and drying at 50 ℃ to obtain 27.55g of compound D, wherein the yield is 82.1%;
(3) synthesis of Compound E
Adding 60.6g of dichloroethane, 27.55g (0.0821mol) of the compound D, 7.77g (0.0903mol) of vinyl acetate and 10.1g (0.0944mol) of sodium carbonate into a reaction bottle, heating to 85 ℃, reacting for 3.5 hours, adding 30.0g of 15% dilute hydrochloric acid to wash twice at the temperature of 25-30 ℃ after the reaction is finished, washing for 15-20min each time, standing and separating to obtain an organic phase, washing once with 30.0g of industrial water, standing and separating again to obtain an organic phase; the organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to give compound E21.5 g, 80.6% yield, 50.23% overall yield over three steps. The overall process yield from the original feedstock to the final product compound E was 40.56%.
Example 5
A preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole comprises the following specific steps:
(1) synthesis of Compound C
To the reaction flask were added 33.5g of DMSO, 154.0g of THF and 52.33g of potassium tert-butoxide, and the temperature was lowered to-15 ℃. Slowly adding a mixed material liquid of 31.75g (0.1333mol) of the compound B, 21.02g of n-butyl nitrite, 30.0g of DMSO and THF100g dropwise, adding dropwise for 2 hours, reacting for 3-4 hours under heat preservation, adding hydrochloric acid dropwise after the reaction is finished, controlling the temperature to be below-5 ℃, distilling the material liquid to recover the solvent, extracting by washing with water, distilling the organic phase to recover the solvent, and obtaining 27.37g of the compound C with the yield of 75.0%.
(2) Synthesis of Compound D
Adding 38.32g of DMF, 27.37g (0.1mol) of compound C and 4.62g (0.0014mol) of sodium tungstate into a reaction bottle, heating to 90 ℃, dropwise adding 128.08g (0.225mol) of sodium hypochlorite, keeping the temperature for reaction for 4.8h, cooling to-5 ℃ after the reaction is finished, performing suction filtration, and drying at 50 ℃ to obtain 27.45g of compound D, wherein the yield is 81.8%;
(3) synthesis of Compound E
Adding 63.13g of toluene, 27.45g (0.0818mol) of compound D, 8.03g (0.0933mol) of vinyl acetate and 9.9g (0.0924mol) of sodium carbonate into a reaction bottle, heating to 85 ℃, reacting for 4 hours, adding 30.0g of 15% dilute hydrochloric acid to perform acid washing twice at the temperature of 25-30 ℃ after the reaction is finished, performing 15-20min each time, standing and separating to obtain an organic phase, washing once with 30.0g of industrial water, standing and separating again to obtain an organic phase; the organic phase was dried over anhydrous sodium sulfate and the solvent removed by rotary evaporation to give compound E21.21 g in 79.5% yield, 48.77% overall yield over three steps. The overall process yield from the original feedstock to the final product compound E was 39.38%.
Comparative example
A preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole is carried out according to the whole technical scheme described in US 2003/0216580A 1, steps 3, 4 and 5 are carried out by the original scheme, the reaction formula is referred to the background technology, and the specific steps are as follows:
(1) synthesis of Compound C-1
Adding 120.0g of acetic acid, 30.00g (0.1149mol) of compound B and 0.7g (0.0023mol) of sodium tungstate into a reaction bottle, heating to 90 ℃, dropwise adding 48.84g (0.4022mol) of 28% hydrogen peroxide, keeping the temperature for reaction for 6.8h, cooling to-5 ℃ after the reaction is finished, carrying out suction filtration, and drying at 50 ℃ to obtain 31.46g of compound C-12, 3-methyl-4-bromobenzenesulfone with the yield of 90.2%;
(2) synthesis of Compound C-2
DMSO 32.77g, THF 151.1g, and potassium tert-butoxide 38.87g were added to the reaction flask and the temperature was reduced to-15 ℃. Slowly adding a mixed feed liquid of a compound C-131.39 g (0.1134mol), n-butyl nitrite 23.83g, DMSO 30.0g and THF100g dropwise, reacting for 3-4h under heat preservation, after the reaction is finished, adding hydrochloric acid dropwise, controlling the temperature below-5 ℃, distilling the feed liquid to recover the solvent, performing water washing extraction, and distilling the organic phase to recover the solvent to obtain 23.51g of a compound C-23-methyl-4-bromobenzylsulfone-2-oxime, wherein the yield is 67.3%.
(3) Synthesis of Compound D
Adding 117.53g of dichloromethane and 0.1037mol of compound C-223.51 g into a reaction bottle, cooling to 0 ℃, introducing chlorine gas for 2.5h, keeping the temperature for reaction for 0.5h, cooling to-5 ℃ after the reaction is finished, performing suction filtration, and drying at 70 ℃ to obtain 33.40g of compound D, wherein the yield is 93.9%;
(4) synthesis of Compound E
153.2g of dichloroethane, 33.40g (0.0973mol) of the compound D and 14.90g (0.146mol) of triethylamine were added to an autoclave, nitrogen gas was substituted for 3 times, ethylene was introduced, pressure was maintained at 2.0MPa, the temperature was raised to 65 ℃ to react for 15 hours, after the reaction was completed, acid washing and water washing were performed, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 23.93g of the compound E, the purity yield was 96.5%, the yield was 74.6%, and the total yield in four steps was 42.523%. The overall process yield from the original feedstock to the final product compound E was 34.34%.
According to the comparison and control of the data of the embodiment and the comparative example, the overall process yield of the method is obviously superior to that of the prior art, and the reaction time is obviously shorter than that of the prior art, so that the method has obvious progress, has obvious advantages in the aspects of safety, environmental protection, cost control and process control, and has great market potential and popularization prospect.
Claims (10)
1. A preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole comprises the preparation of a compound B, and is characterized in that the compound B is used as a starting material, and the subsequent specific steps are as follows:
(3) Adding DMSO, THF and potassium tert-butoxide into a reaction bottle, cooling to-15 ℃, slowly dropwise adding a mixed feed liquid of a compound B, n-butyl nitrite and THF, dropwise adding for 2 hours, reacting for 3-4 hours under heat preservation, dropwise adding hydrochloric acid after the reaction is finished, controlling the temperature below-5 ℃, distilling the feed liquid to recover a solvent, performing water washing extraction, and distilling an organic phase to recover the solvent to obtain a compound C;
(4) adding a reaction solvent, a compound C and a catalyst sodium tungstate into a reaction bottle, heating to a reaction temperature of 80-90 ℃, dropwise adding an oxidant, carrying out heat preservation reaction for 5-6h, cooling to-5 ℃ after the reaction is finished, and carrying out suction filtration to obtain a compound D;
(5) adding a reaction solvent, a compound D, vinyl acetate and sodium carbonate into a reaction bottle, heating to a reaction temperature of 75-85 ℃, reacting for 3-4h, after the reaction is finished, washing a reaction product with 15% dilute hydrochloric acid twice, separating liquid to obtain an organic phase, washing the obtained organic phase once with water, drying with anhydrous sodium sulfate, and performing rotary evaporation to remove the solvent to obtain a compound 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole E, wherein the synthetic route is as follows:
(3) the bromide compound B reacts under the action of an oximation agent to generate an oximation compound C
(4) The oxime compound C reacts under the action of an oxidant to generate an oxime oxygen product compound D:
(5) The oxime oxygen product compound D is subjected to cyclization reaction under the action of vinyl acetate to generate 3- [ 3-bromine-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole E;
2. a process for the preparation of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole according to claim 1, characterized in that compound B is prepared by the following steps:
(1) respectively weighing 2, 3-dimethylaniline, dimethyl disulfide and copper powder in a round-bottom flask at normal temperature, placing the flask in a water bath, heating to 30 ℃, dropwise adding n-butyl nitrite, reacting for 3 hours, and finishing the reaction; filtering the copper powder, distilling the filtrate to recover the solvent, and collecting the fraction above 120 ℃ to obtain a compound A;
(2) adding the compound A and dichloroethane into a reaction bottle, dropwise adding bromine at 25-30 ℃, reacting for 0.5h, adjusting the pH value to 2-3 after the reaction is finished, washing with water at room temperature, drying an organic phase with anhydrous sodium sulfate, and distilling to recover a solvent to obtain a compound B.
3. A process for the preparation of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole according to claim 1,
the reaction solvent in the step (4) is one of ethanol, DMSO and DMF; and the dosage of the reaction solvent is 1.1 to 1.5 times of the mass of the compound C.
4. A process for preparing 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole according to claim 1, wherein the amount of sodium tungstate used as the catalyst in step (4) is 0.1 to 0.15 times the molar amount of compound C.
5. The process for preparing 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole according to claim 1, wherein the oxidizing agent in step (4) is sodium hypochlorite; the addition amount of the oxidant is 2-2.25 times of the molar amount of the compound C.
6. A process for preparing 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole according to claim 1, wherein the reaction solvent in step (5) is one of dichloroethane, toluene, acetonitrile; the dosage of the reaction solvent is 2-2.3 times of the mass of the compound D.
7. A process for preparing 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole according to claim 1, wherein the amount of vinyl acetate used in step (5) is 1.08 to 1.15 times the mass of compound D.
8. A process for preparing 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole according to claim 1, wherein the amount of sodium carbonate used in step (5) is 1.05 to 1.15 times the mass of compound D.
9. A process for preparing 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole according to claim 1, wherein the reaction solvent in step (3) is a mixed solution of DMSO and THF, the amount of DMSO is 1 to 1.1 times the weight of compound B, and the amount of THF is 4.7 to 5 times the weight of compound B;
the dosage of the potassium tert-butoxide is 3.5 times of the molar weight of the compound B;
the dosage of the n-butyl nitrite is 1.5 times of the molar weight of the compound B.
10. A process for the preparation of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole according to claim 1 wherein the acid of step (3) is hydrochloric acid.
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