CN109879817B - Preparation method of mesosulfuron-methyl - Google Patents
Preparation method of mesosulfuron-methyl Download PDFInfo
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Abstract
The invention relates to a method for preparing mesosulfuron, which uses 4-cyano-2-nitrobenzoic acid methyl ester as a starting material, firstly carries out nucleophilic substitution reaction with benzyl mercaptan, then carries out reduction hydrogenation on raney nickel, mesyl chloromethylation, chlorine chlorination, ammonia ammoniation to obtain a key intermediate 2-methoxycarbonyl-5-mesyl aminomethylbenzenesulfonamide, and finally carries out condensation to obtain a target product, namely the mesosulfuron.
Description
Technical Field
The invention relates to synthesis of an organic compound, in particular to a preparation method of mesosulfuron-methyl.
Background
The methyl disulfonsulfuron, also called mesosulfuron, the chemical name 2- [ (4, 6-dimethoxypyrimidine 2-aminocarbonyl) aminosulfonyl ] -a- (methylsulfonylamino) p-toluic acid methyl ester is a novel sulfonylurea herbicide developed by German Bayer company in 2002, and the sulfonylurea herbicide is the largest herbicide in the world, and mainly acts by inhibiting acetolactate synthase, is absorbed by roots and leaves of weeds and is conducted in plants, so that the weeds are promoted to stop growing to achieve the weeding effect. The herbicide has good control effect on part of broadleaf weeds such as annual gramineous weeds and chickweed of winter wheat and spring wheat, and the demand of China on the herbicide market is on a rising trend.
At present, the common synthetic method in the methyl disulfuron market is synthesized by two key intermediates of 4, 6-dimethoxy-2- (phenoxycarbonyl) aminopyrimidine and 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide, wherein the former intermediate is industrialized and is easily available in the market, so how to conveniently and effectively synthesize the key intermediate of 4- (methylsulfonylaminomethyl) 2-krypton sulfonyl methyl benzoate is a primary task.
(1) The earlier method for synthesizing this key intermediate was the 1-tert-butylsulfonamide debutanization. Patent DE4335297 uses 5-methyl-2-methoxycarbonyl benzene sulfonyl chloride as a starting material, firstly amidation reaction is carried out, then NBS bromination, azidation, Pd/C catalytic hydrogenation, further methanesulfonylation is carried out to obtain the angelica-tert-butyl-2 methoxycarbonyl-5-methanesulfonamide methyl benzene sulfonamide, and finally demethylation is carried out under the condition of trifluoro formic acid to obtain a target intermediate, the acidity of the trifluoro formic acid is strong, production equipment is easy to corrode, the raw materials of the route are not easy to obtain, the operation is complex, the use of sodium azide in industrial production increases the risk of experiments and is not beneficial to industrial production.
(2) In order to find a relatively convenient synthetic method, marchand et al improve the synthetic route, patent CN103755603A uses p-tolunitrile as a starting material, firstly reacts with chlorosulfonic acid to obtain sulfonyl chloride for ammoniation, then oxidizes the sulfonyl chloride under the action of potassium dichromate and concentrated acid, then palladium carbon is reduced, methane sulfonylation is performed, and methanol is refluxed to obtain a target intermediate.
(3) At present, the most widely used patent is also Bayer, and US6538150 firstly uses 4-cyano-2-nitrobenzoate as a starting material and uses palladium hydroxide as a catalyst to obtain a key intermediate through reduction hydrogenation, methanesulfonyl chloromethylation and then diazotization reaction, but in the route, precious metals are selected for reduction hydrogenation, the price is high, the catalyst cannot be recycled, and the industrial mass production is limited.
Disclosure of Invention
The purpose is as follows: the invention provides a preparation method of mesosulfuron-methyl, which is simple and convenient to operate, mild in condition and high in yield.
The technical scheme is as follows: in order to solve the technical problems, the technical scheme adopted by the invention is as follows:
according to the invention, nickel is selected to replace noble metal palladium, so that the production cost is greatly reduced, and in one step, benzyl mercaptan is mainly adopted to directly perform nucleophilic substitution reaction, so that the production safety risk is avoided, and the generation of high COD wastewater is reduced.
A method for preparing mesosulfuron, comprising:
taking 4-cyano-2-nitrobenzoic acid methyl ester as a starting material, and carrying out nucleophilic substitution reaction with benzyl mercaptan under an alkaline condition to obtain 2- (benzylthio) -4-cyanobenzoic acid methyl ester (compound 2);
2- (benzylthio) -4-cyanobenzoic acid methyl ester (Compound 2) in H2And Raney nickel as a reducing agent to perform a reduction reaction to obtain 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3);
dripping methanesulfonyl chloride into 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3) to react to obtain 2- (benzylthio) -4- (methylsulfonylaminomethyl) methyl benzoate (compound 4);
chloridizing 2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoic acid methyl ester (compound 4) by chlorine gas, and then ammoniating by ammonia gas to obtain 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide (compound 5);
finally, the 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide (compound 5) and 4, 6-dimethoxy-2- (phenoxycarbonyl) aminopyrimidine are subjected to coupling reaction to obtain a target product of methyldisulfuron.
The method specifically comprises the following steps:
step 1) using 4-cyano-2-nitrobenzoate as a starting material to react with benzyl mercaptan under an alkaline condition to obtain 2- (benzylthio) -4-cyanobenzoate (compound 2), wherein the reaction formula is as follows:
step 2) reaction of methyl 2- (benzylthio) -4-cyanobenzoate (Compound 2) in H2And the reducing agent is Raney nickel, and the reduction reaction is carried out to obtain 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3), wherein the reaction formula is as follows:
step 3) adding methanesulfonyl chloride dropwise into a mixture of 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3), an acid-binding agent and a reaction solvent, and reacting to obtain 2- (benzylthio) -4- (methylsulfonylaminomethyl) methyl benzoate (compound 4), wherein the reaction formula is as follows:
step 4)2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoic acid methyl ester (compound 4) is chloridized under the condition of chlorine gas to obtain sulfonyl chloride, and then ammonia gas is introduced to ammoniate to obtain 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide (compound 5), wherein the reaction formula is as follows:
(3) step 5) 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide (compound 5) and 2-amino-4, 6-dimethylpyrimidine are reacted under the condition of DBU to obtain methyldisulfuron (compound 6), wherein the reaction formula is as follows:
in the step 1), the feeding molar ratio of benzylmercaptan to 4-cyano-2-methyl nitrobenzoate is 1-4; the reaction solvent is preferably DMF; alkaline conditions are provided by dropwise adding sodium hydroxide solution or potassium hydroxide solution, preferably potassium hydroxide solution, the concentration of the potassium hydroxide solution is 10-20%, and the feeding molar ratio of potassium hydroxide to 4-cyano-2-nitrobenzoic acid methyl ester is 1-2.
More preferably, the feeding molar ratio of the benzylthiol to the 4-cyano-2-nitrobenzoic acid methyl ester is 1.16:1, the 4-cyano-2-nitrobenzoic acid methyl ester and the benzylthiol are dissolved in DMF, a 19% potassium hydroxide solution is slowly dripped at 0 ℃, the feeding amount of the potassium hydroxide and the 4-cyano-2-nitrobenzoic acid methyl ester is 1.9, after the dripping is finished, the reaction time is half an hour at room temperature, the reaction is finished, and the mixture is poured into ice water to be filtered to obtain the 2- (benzylthio) -4-cyanobenzoic acid methyl ester (compound 2).
In the step 2), the reducing agent is selected to be Raney nickel, the feeding amount of the Raney nickel is 20-80% of the mass of the 2- (benzylthio) -4-cyanobenzoic acid methyl ester (compound 2), the reaction solvent is methanol which is introduced with ammonia gas to be saturated, the hydrogen pressure is 0.1-5 MPa, the reaction temperature is 10-30 ℃, and the reaction time is 2-5 hours.
More preferably, the 2- (benzylthio) -4-cyanobenzoate (compound 2) is used as a raw material, raney nickel is added, the use amount of raney nickel is preferably 60% of the mass of the 2- (benzylthio) -4-cyanobenzoate (compound 2), the reaction solvent is methanol which is saturated by introducing ammonia, and the hydrogen pressure is 3 MPa; the reaction temperature is preferably 25 ℃ and the reaction time is preferably 3 hours, the reaction is stopped, and further purification is carried out to obtain methyl 4- (aminomethyl) -2- (benzylthio) benzoate (compound 3).
In the step 3), a reaction solvent is dichloromethane, an acid-binding agent can be pyridine or triethylamine, and the adding molar ratio of the acid-binding agent to the 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3) is 1-2; the method for adding methanesulfonyl chloride comprises the steps of dropwise adding at a low temperature of 0-10 ℃, reacting at room temperature for 1-4 hours after dropwise adding, wherein the feeding molar ratio of methanesulfonyl chloride to 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3) is 1-2.
More preferably, the 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3) and an acid-binding agent are dissolved in dichloromethane, the acid-binding agent is preferably triethylamine, the feeding molar ratio of the triethylamine to the 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3) is preferably 1.2, methanesulfonyl chloride is slowly added dropwise under an ice bath, and the feeding molar ratio of the methanesulfonyl chloride to the 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3) is preferably 1.5. After the addition, the reaction is stopped at room temperature preferably for 1 hour, and the reaction product is purified to obtain methyl 2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoate (Compound 4).
In the step 4), firstly, a benzylthio group is replaced to be a sulfonyl chloride group, and a mixed solution of acetic acid and water is selected as a reaction solvent, wherein the volume ratio of the acetic acid to the water is 3-8; chlorine is introduced at a low temperature of 0-10 ℃; then, tetrahydrofuran is used as an ammoniation reaction solvent, and ammonia gas is introduced at a low temperature of 0-10 ℃.
More preferably, methyl 2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoate (compound 4) is mixed with acetic acid and water, the ratio of the acetic acid to the water is preferably 5:1, chlorine is introduced in an ice bath, the introduction of the chlorine is stopped when the amount of the chlorine is solid in the reaction system, the reaction is stopped, ethyl acetate is used for extraction after the reaction is stopped, an organic layer is taken out for spin drying, tetrahydrofuran is added, ammonia is introduced, the reaction is stopped after 10 minutes, and the 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide (compound 5) is obtained by purification.
In the step 5), the feeding molar ratio of the 2-amino-4, 6-methylpyrimidine to the 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide is 1-2; the reaction solvent is acetonitrile; dissolving 2-amino-4, 6-methylpyrimidine and 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide in acetonitrile, and dropwise adding DBU at 0-10 ℃ in an ice bath; the feeding molar ratio of DBU to 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide is 1-2, and the reaction is carried out for 1-2 hours at room temperature after the dropwise addition is finished.
More preferably, the 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide (compound 5) and 2-amino-4, 6-dimethylpyrimidine are dissolved in acetonitrile, the feeding molar ratio of the 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide (compound 5) to the 2-amino-4, 6-dimethylpyrimidine is preferably 1.2, DBU is slowly added dropwise at 0 ℃, the feeding molar ratio of DBU to the 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide (compound 5) is preferably 1.1, and after the addition is finished, the mixture is stirred at room temperature for 2 hours, the reaction is stopped, and the final product methyldisulfuron is obtained through purification.
Has the advantages that: compared with a route for preparing the mesosulfuron-methyl provided by Bayer patents, the synthetic route of the invention has the advantages that firstly, the reaction condition of the route is mild, the operation is convenient, the yield of each step is high, in the first step, the nucleophilic substitution reaction is directly carried out on the starting raw material and benzyl mercaptan, the production safety risk is avoided, and the generation of high-COD wastewater is reduced; compared with Bayer patents, the reducing agent selected in the reduction hydrogenation step of the second step is Raney nickel, so that the price is low, and the cost of industrial production is reduced; the third step is methanesulfonyl chloride, which is environment-friendly and generates no waste; the fourth step uses the mixture of acetic acid and water as solvent, and then introduces chlorine gas, and then introduces ammonia gas to make ammoniation, so that it is low in cost and has no dangerous operation.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
The general synthetic route of mesosulfuron (compound 6) is:
example 1
1) Preparation of methyl 2- (benzylthio) -4-cyanobenzoate (Compound 2)
1g of methyl 4-cyano-2-nitrobenzoate, 700mg of benzyl mercaptan and 10mL of DMF were charged into a 50mL flask, and the resulting solution was hydrated and cooled to 0 ℃. 520mg of potassium hydroxide are dissolved in 2.2ml of H2And O, preparing a potassium hydroxide aqueous solution, and slowly dropwise adding the potassium hydroxide solution into the solution under ice bath. After the completion of the dropwise addition and 30 minutes at room temperature, the reaction was terminated, and the reaction-terminated mixture was poured into ice water, followed by suction filtration to obtain compound 2 as a yellow solid in a yield of 80.1%.
The product data is:1H NMR(400MHz,Chloroform-d)8.01(d,J＝8.0Hz,1H),7.57(d,J＝1.5Hz,1H),7.40(dt,J＝7.9,1.4Hz,3H),7.38–7.23(m,3H),4.15(s,2H),3.91(s,3H)。
2) preparation of methyl 4- (aminomethyl) -2- (benzylthio) benzoate (Compound 3)
Ammonia gas was bubbled through the methanol until it was saturated. 1g of methyl 2- (benzylthio) -4-cyanobenzoate, (600mg, 60% by weight) Raney nickel and 30mL of methanol were charged to the autoclave. Reacting at room temperature for 3 hours under the hydrogen pressure of 3MPa, finishing the reaction, evaporating the solvent, washing residual liquid with water, extracting with ethyl acetate, taking an organic layer, and distilling under reduced pressure to obtain a compound 3 with the yield of 72.6 percent.
The product data is:1H NMR(600MHz,Chloroform-d)7.86(d,J＝8.0Hz,1H),7.35(d,J＝7.5Hz,2H),7.26–7.21(m,3H),7.19(s,1H),7.02(d,J＝8.0Hz,1H),4.12(s,2H),3.82(s,3H),3.79(s,2H)。
3) preparation of methyl 2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoate (Compound 4)
In a 25ml round bottom flask was added 1g of methyl 4- (aminomethyl) -2- (benzylthio) benzoate, 0.56ml of triethylamine, 10ml of dichloromethane, the resulting solution was cooled to 0 ℃ and 0.65m1 of methanesulfonyl chloride was added dropwise to the mixture. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and after the reaction was completed, NaHCO was used3The solution was washed with water, extracted with ethyl acetate and purified by column chromatography to give compound 4 in 78.6% yield.
The product data is:1H NMR(600MHz,Chloroform-d)7.87(dd,J＝8.0,1.5Hz,1H),7.36(d,J＝7.5Hz,2H),7.25–7.23(m,3H),7.19(q,J＝4.1,3.4Hz,1H),7.02(d,J＝8.1Hz,1H),4.70(t,J＝6.3Hz,1H),4.21(d,J＝6.3Hz,2H),4.10(s,2H),3.83(d,J＝1.5Hz,3H),2.71(d,J＝1.6Hz,3H)。
4) preparation of 2-methoxycarbonyl-5-methanesulfonylaminomethyl benzenesulfonamide (Compound 5)
1g of methyl 2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoate, 6ml of acetic acid and 1.2ml of water were charged into a 25m1 round-bottomed flask, and the reaction was stopped by introducing chlorine gas in an ice bath until the solid in the reaction system disappeared. Ethyl acetate extraction, organic phases are combined, and the organic phase is concentrated under reduced pressure without further purification to obtain a crude intermediate compound, namely methyl 2- (chlorosulfonyl) -4- (methylsulfonaminomethyl) benzoate. The intermediate compound methyl 2- (chlorosulfonyl) -4- (methylsulfonylaminomethyl) benzoate and 10ml tetrahydrofuran were added to a 25ml round-bottomed flask, ammonia gas was introduced in an ice bath, the reaction was completed for 10 minutes, the solvent was evaporated to give a white solid, which was washed with methanol and water to give compound 5 in 72.4% yield.
The product data is:1H NMR(400MHz,Acetone-d6)8.08–8.05(m,1H),7.82(d,J＝7.9Hz,1H),7.75(ddt,J＝7.8,1.6,0.8Hz,1H),6.76(s,1H),6.61(s,2H),4.47(dt,J＝6.5,0.8Hz,2H),3.93(s,3H),2.96(s,3H)。
5) preparation of Mesosulfuron (Compound 6)
Dissolving 1g of 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide and 1.02g of 4, 6-dimethoxy-2- (phenoxycarbonyl) aminopyrimidine in 10ml of acetonitrile, cooling to 0 ℃ in an ice bath, slowly dropwise adding 520mg of DBU, stirring at room temperature for 1 hour after dropwise adding, finishing the reaction, spin-drying the solvent, adding 7ml of 2N HCl into residual liquid, a small amount of methanol, precipitating a large amount of solid, and carrying out suction filtration to obtain a compound 6 with the yield of 83.6%.
The product data is:1H NMR(400MHz,Chloroform-d)12.66(s,1H),8.39(d,J＝1.3Hz,1H),7.80(s,1H),7.72(t,J＝1.0Hz,2H),5.78(s,1H),5.61(t,J＝6.5Hz,1H),4.47(d,J＝6.5Hz,2H),3.98(s,6H),3.88(s,3H),2.94(s,3H)。
example 2
1) Preparation of methyl 2- (benzylthio) -4-cyanobenzoate (Compound 2)
5g of methyl 4-cyano-2-nitrobenzoate, 3.5g of benzyl mercaptan and 45mL of DMF were added to a 250mL flask and the resulting solution was hydrated and cooled to 0 ℃. 2.6g of potassium hydroxide are dissolved in 11ml of H2And O, preparing a potassium hydroxide aqueous solution, and slowly dropwise adding the potassium hydroxide solution into the solution under ice bath. After the dropwise addition, the reaction is carried out for 30 minutes at room temperature, the reaction is finished, the mixture after the reaction is finished is poured into ice water, and then the yellow solid, namely the compound 2, is obtained through suction filtration, and the yield is over 80%.
The product data is:1H NMR(400MHz,Chloroform-d)8.01(d,J＝8.0Hz,1H),7.57(d,J＝1.5Hz,1H),7.40(dt,J＝7.9,1.4Hz,3H),7.38–7.23(m,3H),4.15(s,2H),3.91(s,3H)。
2) preparation of methyl 4- (aminomethyl) -2- (benzylthio) benzoate (Compound 3)
Ammonia gas was bubbled through the methanol until it was saturated. 5g of methyl 2- (benzylthio) -4-cyanobenzoate, (1.5g, 60% by weight) Raney nickel and 100mL of methanol were charged into the autoclave. Reacting at room temperature for 3 hours under the hydrogen pressure of 3MPa, finishing the reaction, evaporating the solvent, washing with water, extracting with ethyl acetate, and distilling the organic layer under reduced pressure to obtain the compound 3 with the yield of more than 70%.
The product data is:1H NMR(600MHz,Chloroform-d)7.86(d,J＝8.0Hz,1H),7.35(d,J＝7.5Hz,2H),7.26–7.21(m,3H),7.19(s,1H),7.02(d,J＝8.0Hz,1H),4.12(s,2H),3.82(s,3H),3.79(s,2H)。
3) preparation of methyl 2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoate (Compound 4)
In a 100ml round-bottom flask was added 5g of methyl 4- (aminomethyl) -2- (benzylthio) benzoate, 2.8ml of triethylamine, 35ml of dichloromethane, the resulting solution was cooled to 0 ℃ and 3.4m1 of methanesulfonyl chloride was added dropwise to the mixture. After the dropwise addition, the mixture was stirred at room temperature for 1 hour, and after the reaction was completed, NaHCO was used3The solution was washed with water, extracted with ethyl acetate and purified by column chromatography to give compound 4 with a yield of over 70%.
The product data is:1H NMR(600MHz,Chloroform-d)7.87(dd,J＝8.0,1.5Hz,1H),7.36(d,J＝7.5Hz,2H),7.25–7.23(m,3H),7.19(q,J＝4.1,3.4Hz,1H),7.02(d,J＝8.1Hz,1H),4.70(t,J＝6.3Hz,1H),4.21(d,J＝6.3Hz,2H),4.10(s,2H),3.83(d,J＝1.5Hz,3H),2.71(d,J＝1.6Hz,3H)。
4) preparation of 2-methoxycarbonyl-5-methanesulfonylaminomethyl benzenesulfonamide (Compound 5)
5g of methyl 2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoate, 30ml of acetic acid and 6ml of water are added into a 100m1 round-bottom flask, chlorine is introduced at 0-10 ℃ until the solid in the reaction system disappears, and the reaction is stopped. Ethyl acetate extraction, organic phases are combined, and the organic phase is concentrated under reduced pressure without further purification to obtain a crude intermediate compound, namely methyl 2- (chlorosulfonyl) -4- (methylsulfonaminomethyl) benzoate. The intermediate compound methyl 2- (chlorosulfonyl) -4- (methylsulfonylaminomethyl) benzoate and 35ml tetrahydrofuran were added to a 100ml round-bottom flask, ammonia gas was introduced in an ice bath, and the solvent was evaporated to give a white solid, which was washed with methanol and water to give compound 5 in a yield of 60% or more.
The product data is:1H NMR(400MHz,Acetone-d6)8.08–8.05(m,1H),7.82(d,J＝7.9Hz,1H),7.75(ddt,J＝7.8,1.6,0.8Hz,1H),6.76(s,1H),6.61(s,2H),4.47(dt,J＝6.5,0.8Hz,2H),3.93(s,3H),2.96(s,3H)。
5) preparation of Mesosulfuron (Compound 6)
Dissolving 5g of 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide and 5.2g of 4, 6-dimethoxy-2- (phenoxycarbonyl) aminopyrimidine in 40ml of acetonitrile, cooling to 0 ℃ in an ice bath, slowly dropwise adding 2.6g of DBU, stirring for 1 hour at room temperature after dropwise adding is finished, finishing the reaction, drying the solvent by spinning, adding 35ml of 2N HCl and a small amount of methanol into residual liquid, separating out a large amount of solid, and performing suction filtration to obtain a compound 6 with the yield of over 80%.
The product data is:1H NMR(400MHz,Chloroform-d)12.66(s,1H),8.39(d,J＝1.3Hz,1H),7.80(s,1H),7.72(t,J＝1.0Hz,2H),5.78(s,1H),5.61(t,J＝6.5Hz,1H),4.47(d,J＝6.5Hz,2H),3.98(s,6H),3.88(s,3H),2.94(s,3H)。
the above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.
Claims (15)
1. A method for preparing mesosulfuron, which is characterized by comprising the following steps:
taking 4-cyano-2-nitrobenzoic acid methyl ester as a starting material, and carrying out nucleophilic substitution reaction with benzyl mercaptan under an alkaline condition to obtain 2- (benzylthio) -4-cyanobenzoic acid methyl ester;
2- (benzylthio) -4-cyanobenzoic acid methyl ester in H2And Raney nickel as a reducing agent to perform a reduction reaction to obtain 4- (aminomethyl) -2- (benzylthio) methyl benzoate (compound 3);
dripping methanesulfonyl chloride into 4- (aminomethyl) -2- (benzylthio) methyl benzoate to react to obtain 2- (benzylthio) -4- (methylsulfonylaminomethyl) methyl benzoate;
chloridizing 2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoic acid methyl ester by using chlorine gas, and then ammoniating to obtain 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide;
finally, the 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide and 4, 6-dimethoxy-2- (phenoxycarbonyl) aminopyrimidine are subjected to coupling reaction to obtain a target product of methyldisulfuron.
2. The method for preparing mesosulfuron according to claim 1, comprising the following steps:
step 1) using 4-cyano-2-nitrobenzoate as a starting material to react with benzyl mercaptan under an alkaline condition to obtain 2- (benzylthio) -4-cyanobenzoate methyl ester, namely a compound 2, wherein the reaction formula is as follows:
step 2) preparation of methyl 2- (benzylthio) -4-cyanobenzoate in H2And the reducing agent is Raney nickel, and the reducing reaction is carried out to obtain 4- (aminomethyl) -2- (benzylthio) methyl benzoate, namely a compound 3, and the reaction formula is as follows:
step 3) dripping methanesulfonyl chloride into a mixture of 4- (aminomethyl) -2- (benzylthio) methyl benzoate, an acid-binding agent and a reaction solvent to react to obtain 2- (benzylthio) -4- (methylsulfonylaminomethyl) methyl benzoate, namely a compound 4, according to a reaction formula:
step 4), chlorinating methyl 2- (benzylthio) -4- (methylsulfonylaminomethyl) benzoate under the condition of chlorine to obtain sulfonyl chloride, then introducing ammonia gas to perform ammoniation to obtain 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide, namely a compound 5, wherein the reaction formula is as follows:
step 5) 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide and 2-amino-4, 6-dimethylpyrimidine are reacted under DBU to obtain methyldisulfuron, namely a compound 6, according to the reaction formula:
3. the method for preparing mesosulfuron according to claim 2, wherein the molar ratio of benzyl mercaptan to methyl 4-cyano-2-nitrobenzoate used in step 1) is 1 to 4.
4. The process for preparing mesosulfuron according to claim 2, wherein in step 1), the reaction solvent is DMF.
5. The method for preparing mesosulfuron according to claim 2, wherein the alkaline condition is provided by dropwise addition of a sodium hydroxide solution or a potassium hydroxide solution in step 1).
6. The method for preparing mesosulfuron according to claim 5, wherein the alkaline condition is potassium hydroxide solution, the concentration of the potassium hydroxide solution is selected to be 10-20%, and the molar ratio of potassium hydroxide to methyl 4-cyano-2-nitrobenzoate is 1-2.
7. The method for preparing methyldisulfuron according to claim 2, characterized in that in step 2), the input amount of raney nickel is 20-80% of the mass of 2- (benzylthio) -4-cyanobenzoic acid methyl ester (compound 2).
8. The method for preparing mesosulfuron according to claim 2, wherein in step 2), ammonia gas is introduced into the reaction solvent to saturate methanol, the hydrogen pressure is 0.1 to 5MPa, the reaction temperature is 10 to 30 ℃, and the reaction time is 2 to 5 hours.
9. The process for preparing mesosulfuron according to claim 2, wherein the reaction solvent used in step 3) is dichloromethane.
10. The method for preparing mesosulfuron according to claim 2, wherein in step 3), pyridine or triethylamine is used as the acid-binding agent, and the molar ratio of the acid-binding agent to the methyl 4- (aminomethyl) -2- (benzylthio) benzoate is 1-2.
11. The method for preparing methyldisulfuron according to claim 2, characterized in that in step 3), the methanesulfonyl chloride is added dropwise at a low temperature of 0-10 ℃, and after the dropwise addition, the reaction is carried out at room temperature for 1-4 hours, and the feeding molar ratio of methanesulfonyl chloride to methyl 4- (aminomethyl) -2- (benzylthio) benzoate is 1-2.
12. The method for preparing methyldisulfuron according to claim 2, characterized in that in the step 4), firstly, a mixed solution of acetic acid and water is selected as a reaction solvent for substituting benzylthio for sulfonyl chloride group, wherein the volume ratio of acetic acid to water is 3-8; chlorine is introduced at a low temperature of 0-10 ℃.
13. The method for preparing mesosulfuron according to claim 2, wherein in step 4), tetrahydrofuran is used as the ammoniation reaction solvent, and ammonia gas is introduced at a low temperature of 0-10 ℃.
14. The method for preparing mesosulfuron according to claim 2, wherein in step 5), the molar ratio of 2-amino-4, 6-methylpyrimidine to 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide is 1 to 2; the reaction solvent is acetonitrile.
15. The process for preparing methyldisulfuron according to claim 14, characterized in that 2-amino-4, 6-methylpyrimidine and 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide are dissolved in acetonitrile, and DBU is added dropwise at 0 to 10 ℃ in an ice bath;
the feeding molar ratio of DBU to 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide is 1-2, and the reaction is carried out for 1-2 hours at room temperature after the dropwise addition is finished.
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