CN110452139B - Preparation method of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile - Google Patents
Preparation method of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile Download PDFInfo
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Abstract
The invention belongs to the technical field of organic synthesis. 2, 3-dimethyl-p-bromobenzenesulfone is taken as a raw material, is appropriately heated in nitrite, organic strong base and polar aprotic solvent to carry out one-pot reaction, and is extracted and purified to obtain a target product. The invention relates to a preparation method of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile, which is a one-step synthesis process and comprises the following steps of synthesis, separation and purification: dissolving 2, 3-dimethyl-p-bromobenzenesulfone and excessive organic strong base in polar aprotic solvent, cooling to-5 ℃, dropwise adding nitrite while stirring, heating to 20-50 ℃ after dropwise adding, reacting for 7-12h, and performing extraction separation and recrystallization to obtain the target product. The preparation method of the 2-methyl-3-bromo-6-methylsulfonyl benzonitrile provided by the invention has the advantages of high selectivity to 2-methyl, short flow, concise post-treatment, simple and convenient operation, energy conservation and environmental protection, is suitable for industrial production of the 2-methyl-3-bromo-6-methylsulfonyl benzonitrile, and has guiding significance for cyanidation of a dimethyl aromatic ring compound containing an electron-withdrawing group.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, relates to an arylmethyl substitution technology, and particularly relates to a preparation technology of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile.
Background
2-methyl-3-bromo-6-methylsulfonyl benzonitrile is a relatively new compound, and no research on preparation is found at home and abroad. The researches on changing methyl on an aromatic ring into cyano are mainly as follows at home and abroad:
(1) an ammonia oxidation method: the process has more domestic researches, and the industrialization of converting toluene into benzonitrile has certain advantages;
(2) side chain methyl substitution: adopting NBS, chlorine and the like to halogenate the side chain, then oxidizing the side chain into aldehyde, and directly reacting the aldehyde with hydrocyanic acid to obtain a product;
(3) side chain methyl redox: the side chain methyl group is directly oxidized into acid, then reduced into aldehyde by using a catalyst, and then reacted with hydrocyanic acid to obtain a product.
The three processes are only directed to the case of one methyl group on an aromatic ring, and the case of a compound containing two or more methyl groups is not reported in the literature.
Disclosure of Invention
The invention aims to provide a method for preparing 2-methyl-3-bromo-6-methylsulfonyl benzonitrile by a one-pot method.
The invention aims to realize the purpose that 2, 3-dimethyl-p-bromobenzenesulfone is taken as a raw material, the raw material is properly heated in nitrite, organic strong base and polar aprotic solvent to carry out one-pot reaction, and a target product is obtained through extraction and purification.
The invention relates to a preparation method of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile, which comprises the following synthetic routes:
comprises the processes of one-step synthesis, separation and purification. The method comprises the following specific steps:
(1) synthesizing by a one-step method: dissolving 2, 3-dimethyl-p-bromobenzenesulfone and excessive organic strong base in polar aprotic solvent, cooling to-5-5 ℃, dropwise adding nitrite while stirring, and heating to 20-50 ℃ after dropwise adding to react for 7-12 h;
(2) separation: slowly adding acid to neutralize excessive alkali until the pH value is 3-5, removing the reaction solvent, extracting and separating the mixture by using water and lower halogenated hydrocarbon, washing an organic phase by using water, drying the organic phase, and then removing the solvent by rotary evaporation to obtain a crude product of the 2-methyl-3-bromo-6-methylsulfonyl benzonitrile;
(3) and (3) purification: heating and dissolving the crude product of the 2-methyl-3-bromo-6-methylsulfonyl benzonitrile in an alcohol solvent, removing insoluble substances through heat filtration, and cooling and crystallizing to obtain the target product of the 2-methyl-3-bromo-6-methylsulfonyl benzonitrile.
The organic alkali is one of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and the molar amount of the organic alkali is 2.5-4 times that of 2, 3-dimethyl-p-bromobenzenesulfone.
The acid is one of analytically pure formic acid, analytically pure acetic acid and 10-20% hydrochloric acid aqueous solution.
The polar aprotic solvent is one or a mixed solvent of tetrahydrofuran, dimethyl sulfoxide and dimethylformamide, and the dosage of the polar aprotic solvent is at least 1.5 times of the mass of 2, 3-dimethyl-p-bromobenzenesulfone.
The nitrite is one of n-butyl nitrite, tert-butyl nitrite, n-propyl nitrite and isopropyl nitrite, and the molar amount of the nitrite is 1.05-2.0 times of that of 2, 3-dimethyl-p-bromobenzenesulfone.
The lower halogenated hydrocarbon used for extraction in the separation process is one of chloroform, dichloromethane and dichloroethane, and the dosage is at least 2 times of the mass of 2, 3-dimethyl-p-bromobenzenesulfone.
The amount of the extraction water used in each time in the separation process is at least 1.5 times of the mass of the 2, 3-dimethyl-p-bromobenzenesulfone.
The alcohol solvent for recrystallization is one of methanol, ethanol, n-propanol, isopropanol and n-butanol; the dosage is 0.5-2.0 times of the crude product.
The drying agent for drying the organic phase is one of anhydrous sodium sulfate, anhydrous magnesium sulfate and anhydrous calcium chloride.
The preparation method of the 2-methyl-3-bromo-6-methylsulfonyl benzonitrile provided by the invention has the advantages of high selectivity to 2-methyl, short flow, concise post-treatment, simple and convenient operation, energy conservation and environmental protection, is suitable for industrial production of the 2-methyl-3-bromo-6-methylsulfonyl benzonitrile, and has guiding significance for cyanidation of a dimethyl aromatic ring compound containing an electron-withdrawing group.
Drawings
FIG. 1 shows nuclear magnetic hydrogen spectrum of a target product 2-methyl-3-bromo-6-methylsulfonyl benzonitrile in an embodiment of the present invention
Detailed Description
The above-described aspects of the present invention are further illustrated by the following specific examples, which should not be construed as limiting the scope of the above-described subject matter of the present invention to the examples below. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1
At normal temperature, 27.7g of 2, 3-dimethyl-p-bromobenzenesulfone with the content of 95 percent is weighed,Dissolving 21.8g of sodium methoxide, 30g of tetrahydrofuran and 12g of dimethyl sulfoxide in a 250ml round-bottom flask, placing the flask in a low-temperature tank, stirring, cooling to-5 ℃, and keeping the temperature at 0 DEG C-18.0g of isopropyl nitrite was added dropwise at-5 ℃. After the liquid phase tracking raw material reaction is finished, placing the bottle in a water bath, heating to 50 ℃, preserving heat and reacting for 12 hours, and finishing the reaction.
Cooling the reaction system to room temperature, dropwise adding analytically pure acetic acid to adjust the pH value to 5, carrying out rotary evaporation to remove the solvent, adding 42g of water and 55g of dichloromethane to carry out extraction, washing the organic phase with 42g of water once again, extracting the organic phase, drying with anhydrous sodium sulfate, and carrying out rotary evaporation to remove the solvent to obtain 28.5g of a crude product.
28.5g of ethanol is added into the crude product, the mixture is heated to reflux, insoluble substances are removed by heat filtration, and the mixture is cooled to 0 ℃ for crystallization to obtain 18.1g of gray brown solid powder, namely 2-methyl-3-bromo-6-methylsulfonylbenzonitrile, with the yield of 63.4%. The nuclear magnetic quantification product content was 96%. The molecular weight calculated by Chemdraw is 274.13, the melting point measured by a melting point instrument is 145 ℃, and the nuclear magnetic hydrogen spectrum measured by Bruker 400M nuclear magnetic is shown in figure 1.
Example 2
At normal temperature, 27.7g of 95% 2, 3-dimethyl-p-bromobenzenesulfone, 24.3g of sodium tert-butoxide, 30g of tetrahydrofuran and 12g of dimethyl sulfoxide are weighed into a 250ml round-bottom flask, the flask is placed into a low-temperature tank after being dissolved, the temperature is reduced to 5 ℃ by stirring, and then 15.45g of n-butyl nitrite is weighed and added into the reaction system. After the liquid phase tracking raw material reaction is finished, placing the bottle in a water bath, heating to 20 ℃, preserving heat and reacting for 7 hours, and finishing the reaction.
Cooling the reaction system to room temperature, dropwise adding acetic acid to adjust the pH value to 4, removing the solvent by rotary evaporation, adding 42g of water and 55g of dichloroethane for extraction, washing the organic phase with 50g of water once again, extracting the organic phase, drying the organic phase with anhydrous sodium sulfate, and removing the solvent by rotary evaporation to obtain 27.3g of a crude product.
Adding 30g of ethanol into the crude product, heating to reflux, carrying out heat filtration to remove insoluble substances, cooling to 0 ℃ and crystallizing to obtain 10.7g of a 92% gray-brown product, wherein the yield is 35.9%, the molecular weight is 274.13, and the melting point is 145 ℃.
Example 3
At normal temperature, 27.7g of 2, 3-dimethyl-p-bromobenzenesulfone with the content of 95%, 33.9g of potassium tert-butoxide and 42g of dimethylformamide are weighed and placed in a 250ml round-bottom flask, after dissolution, the flask is placed in a low-temperature tank, the temperature is reduced to 0 ℃ by stirring, and then 13.5g of n-propyl nitrite is weighed and added into the reaction system dropwise. Placing the bottle in a water bath, heating to 40 ℃, and reacting for 9 hours under the condition of heat preservation.
Cooling the reaction system to room temperature, dropwise adding acetic acid to adjust the pH value to 5, removing the solvent by rotary evaporation, adding 42g of water and 55g of chloroform for extraction, washing the organic phase with 45g of water once, extracting the organic phase, drying over anhydrous magnesium sulfate, and removing the solvent by rotary evaporation to obtain 27.1g of a crude product.
Adding 25g of methanol into the crude product, heating to 60 ℃, carrying out hot filtration to remove raw materials and insoluble substances, cooling to 0 ℃ for crystallization, and obtaining 13.27g of a target product with the content of 97%, the yield of 47.0%, the molecular weight of 274.13 and the melting point of 145 ℃.
Example 4
At normal temperature, 27.7g of 95% 2, 3-dimethyl-p-bromobenzenesulfone, 38.4g of sodium tert-butoxide, 32g of tetrahydrofuran and 12g of dimethylformamide are weighed and placed in a 250ml round-bottom flask, after dissolution, the flask is placed in a low-temperature tank, the temperature is reduced to 2 ℃ by stirring, and then 9.5g of isopropyl nitrite is weighed and added into the reaction system. After the liquid phase tracking raw material reaction is finished, placing the bottle in a water bath, heating to 50 ℃, preserving heat and reacting for 10 hours, and finishing the reaction.
Cooling the reaction system to room temperature, dropwise adding 10% hydrochloric acid solution to adjust the pH value to 3, removing the organic solvent by rotary evaporation, adding 45g of water and 70g of dichloromethane for extraction, washing the organic phase with 42g of water once, extracting the organic phase, drying anhydrous calcium chloride, and removing the solvent by rotary evaporation to obtain 28.1g of a crude product.
Adding 28.1g of n-butanol into the crude product, heating to 80 ℃, carrying out heat filtration to remove insoluble substances, cooling to 2 ℃ for crystallization, and obtaining 18.9g of a target product with the content of 96%, the yield of 66.2%, the molecular weight of 274.13 and the melting point of 145 ℃.
Example 5
At normal temperature, 27.7g of 95% 2, 3-dimethyl-p-bromobenzenesulfone, 13.5g of sodium methoxide, 30g of tetrahydrofuran and 22g of dimethylformamide are weighed and placed in a 250ml round-bottom flask, after dissolution, the flask is placed in a low-temperature tank, the temperature is reduced to-3 ℃ by stirring, and then 11.5g of n-propyl nitrite is weighed and added into the reaction system in a dropwise manner. After the dropwise addition, the bottle was placed in a water bath, heated to 25 ℃ and reacted for 8 hours with heat preservation. Cooling the reaction system to room temperature, dropwise adding 20% hydrochloric acid solution to adjust the pH value to 5, removing the organic solvent by rotary evaporation, adding 48g of water and 60g of dichloromethane for extraction, washing the organic phase with 42g of water once, extracting the organic phase, drying with anhydrous sodium sulfate, and removing the solvent by rotary evaporation to obtain 27.3g of a crude product.
Adding 54.6g of isopropanol into the crude product, heating to 60 ℃, carrying out hot filtration to remove raw materials, cooling to 0 ℃ for crystallization to obtain 10.2g of a target product with the content of 90%, wherein the product is brownish black, the yield is 33.5%, the molecular weight is 274.13, and the melting point is 145 ℃.
Example 6
At normal temperature, 27.7g of 95 percent 2, 3-dimethyl-p-bromobenzenesulfone, 20.6g of sodium ethoxide and 42g of dimethyl sulfoxide are weighed in a 250ml round-bottom flask, the flask is placed in a low-temperature tank after being dissolved, the temperature is reduced to 5 ℃ by stirring, and then 9.3g of isopropyl nitrite is weighed and added into a reaction system. After the liquid phase tracking raw material reaction is finished, placing the bottle in a water bath, heating to 35 ℃, preserving the temperature, reacting for 10.5h, and finishing the reaction.
Cooling the reaction system to room temperature, dropwise adding formic acid to adjust the pH value to 3, removing the solvent by rotary evaporation, adding 42g of water and 55g of dichloroethane for extraction, washing the organic phase with 42g of water once again, extracting the organic phase, drying the organic phase with anhydrous sodium sulfate, and removing the solvent by rotary evaporation to obtain 29.9g of a crude product.
Adding 30g of n-propanol into the crude product, heating to reflux, carrying out hot filtration to remove insoluble substances, cooling to 3 ℃ and crystallizing to obtain 17.4g of a target product with the content of 93%, the yield of 59.0%, the molecular weight of 274.13 and the melting point of 145 ℃.
Example 7
At normal temperature, 27.7g of 95 percent 2, 3-dimethyl-p-bromobenzenesulfone, 13.5g of sodium methoxide and 42g of tetrahydrofuran are weighed and placed in a 250ml round-bottom flask, after the 2, 3-dimethyl-p-bromobenzenesulfone, the flask is placed in a low-temperature tank after the sodium methoxide and the tetrahydrofuran are dissolved, the temperature is reduced to-2 ℃ by stirring, and then 12.7g of isopropyl nitrite is weighed and added into a reaction system. After the liquid phase tracking raw material reaction is finished, placing the bottle in a water bath, heating to 30 ℃, preserving heat and reacting for 11 hours, and finishing the reaction.
Cooling the reaction system to room temperature, dropwise adding 15% hydrochloric acid solution to adjust the pH value to 4, removing the solvent by rotary evaporation, adding 50g of water and 80g of dichloromethane for extraction, washing the organic phase with 42g of water once again, extracting the organic phase, drying the organic phase with anhydrous sodium sulfate, and removing the solvent by rotary evaporation to obtain 26.6g of a crude product.
Adding 26g of ethanol into the crude product, heating to reflux, carrying out heat filtration to remove insoluble substances, cooling to 0 ℃ and crystallizing to obtain 12.1g of a target product with the content of 96%, the yield of 42.4%, the molecular weight of 274.13 and the melting point of 145 ℃.
Example 8
At normal temperature, 27.7g of 95% 2, 3-dimethyl-p-bromobenzenesulfone, 29.1g of sodium tert-butoxide, 20g of tetrahydrofuran and 22g of dimethyl sulfoxide are weighed into a 250ml round-bottom flask, the flask is placed into a low-temperature tank after being dissolved, the temperature is reduced to 4 ℃ by stirring, and then 15.0g of tert-butyl nitrite is weighed and added into the reaction system. After the liquid phase tracking raw material reaction is finished, placing the bottle in a water bath, heating to 45 ℃, preserving the temperature, reacting for 10 hours, and finishing the reaction.
Cooling the reaction system to room temperature, dropwise adding acetic acid to adjust the pH value to 5, removing the solvent by rotary evaporation, adding 42g of water and 55g of dichloromethane for extraction, washing the organic phase with 42g of water once again, extracting the organic phase, drying over anhydrous magnesium sulfate, and removing the solvent by rotary evaporation to obtain 28.8g of a crude product.
Adding 28.8g of methanol into the crude product, heating to reflux, removing insoluble substances by heat filtration, and cooling to 0 ℃ for crystallization to obtain 15.5g of a target product with the content of 96.5 percent, the yield is 54.6 percent, the molecular weight is 274.13, and the melting point is 145 ℃.
Example 9
At normal temperature, 27.7g of 95 percent 2, 3-dimethyl-p-bromobenzenesulfone, 21.6g of sodium methoxide, 50g of tetrahydrofuran and 12g of dimethyl sulfoxide are weighed and placed in a 250ml round-bottom flask, after dissolution, the flask is placed in a low-temperature tank, the temperature is reduced to-5 ℃ by stirring, and then 20.6g of tert-butyl nitrite is weighed and added into a reaction system. After the liquid phase tracking raw material reaction is finished, placing the bottle in a water bath, heating to 50 ℃, preserving heat and reacting for 7.8h, and finishing the reaction.
Cooling the reaction system to room temperature, dropwise adding 10% hydrochloric acid to adjust the pH value to 5, removing the solvent by rotary evaporation, adding 42g of water and 55g of dichloromethane for extraction, washing the organic phase with 42g of water once again, extracting the organic phase, drying with anhydrous sodium sulfate, and removing the solvent by rotary evaporation to obtain 25.8g of a crude product.
Adding 12.9g of ethanol into the crude product, heating to reflux, carrying out hot filtration to remove insoluble substances, cooling to 0 ℃ for crystallization, and obtaining 16.0g of a target product with the content of 96%, the yield of 56.1%, the molecular weight of 274.13 and the melting point of 145 ℃.
Claims (6)
1. A preparation method of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile is a one-step synthesis process, comprises the processes of synthesis, separation and purification, and comprises the following specific steps:
(1) synthesizing: dissolving 2, 3-dimethyl-p-bromobenzenesulfone and excessive organic strong base in a polar aprotic solvent, cooling to-5 ℃, dropwise adding excessive nitrite while stirring, and raising the temperature to 20-50 ℃ after dropwise adding to react for 7-12 h;
(2) separation: slowly adding acid to neutralize excessive alkali until the pH value is 3-5, removing a reaction solvent, extracting and separating water and lower halogenated hydrocarbon, washing an organic phase with water, drying, and removing the solvent by rotary evaporation to obtain a crude product of the 2-methyl-3-bromo-6-methylsulfonyl benzonitrile;
(3) and (3) purification: heating and dissolving the crude product of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile in an alcohol solvent, removing insoluble substances by heat filtration, and cooling and crystallizing to obtain a target product of 2-methyl-3-bromo-6-methylsulfonyl benzonitrile;
wherein: the nitrite is isopropyl nitrite;
the organic strong base is one of sodium methoxide and sodium tert-butoxide; the polar aprotic solvent is one or a mixed solvent of tetrahydrofuran, dimethyl sulfoxide and dimethylformamide;
the acid is one of formic acid, acetic acid and 10-20% hydrochloric acid aqueous solution;
the molar consumption of the nitrite is 1.05-2.0 times of that of the 2, 3-dimethyl-p-bromobenzenesulfone;
the molar amount of the organic strong base is 3.5-4 times that of the 2, 3-dimethyl-p-bromobenzenesulfone;
the lower halogenated hydrocarbon used for extraction in the separation process is one of chloroform, dichloromethane and dichloroethane.
2. The method for producing 2-methyl-3-bromo-6-methylsulfonylbenzonitrile as claimed in claim 1, wherein the amount of the polar aprotic solvent is at least 1.5 times the mass of 2, 3-dimethyl-p-bromophenylsulfone.
3. The process for producing 2-methyl-3-bromo-6-methylsulfonylphenylnitrile as claimed in claim 1, wherein the amount of the lower halogenated hydrocarbon used for the extraction in the separation process is at least 2 times the mass of 2, 3-dimethyl-p-bromophenylsulfone.
4. The method for preparing 2-methyl-3-bromo-6-methylsulfonylphenylnitrile as claimed in any one of claims 1 to 2, wherein the alcohol solvent used for dissolution in the purification process is one of methanol, ethanol, n-propanol, isopropanol and n-butanol.
5. The method for preparing 2-methyl-3-bromo-6-methylsulfonylphenylnitrile as claimed in any one of claims 1 to 2, characterized in that the amount of extraction water used in the separation process is at least 1.5 times the mass of 2, 3-dimethyl-p-bromophenylsulfone.
6. The method for preparing 2-methyl-3-bromo-6-methylsulfonylbenzonitrile as claimed in any one of claims 1 to 2, wherein the drying agent is one of anhydrous sodium sulfate, anhydrous magnesium sulfate and anhydrous calcium chloride.
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| CN101065353A (en) * | 2004-11-26 | 2007-10-31 | 巴斯福股份公司 | Novel 2-cyano-3-(halo)alkoxy-benzenesulfonamide compounds for combating animal pests |
| US20140275159A1 (en) * | 2013-03-14 | 2014-09-18 | Boehringer Ingelheim International Gmbh | Substituted 2-aza-bicyclo[2.2.2]octane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101065353A (en) * | 2004-11-26 | 2007-10-31 | 巴斯福股份公司 | Novel 2-cyano-3-(halo)alkoxy-benzenesulfonamide compounds for combating animal pests |
| US20140275159A1 (en) * | 2013-03-14 | 2014-09-18 | Boehringer Ingelheim International Gmbh | Substituted 2-aza-bicyclo[2.2.2]octane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c |
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