CN109879817B - Preparation method of mesosulfuron-methyl - Google Patents

Abstract

The invention relates to a method for preparing methyldisulfuron. 4-cyano-2-nitrobenzoic acid methyl ester is used as a starting material, firstly, a nucleophilic substitution reaction is carried out with benzyl mercaptan, and then Raney nickel is reduced and hydrogenated , methanesulfonyl chloride methanesulfonylation, then chlorine chlorination, ammonia amination to obtain the key intermediate 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide, and finally condensation to obtain the target product methyldicarbonate Sulfuron-methyl, the reaction process conditions of this route are mild, easy to operate, suitable for large-scale industrial production, and less polluting to the environment, and it is a better new method for synthesizing methyldisulfuron-methyl.

Description

The preparation method of methyldisulfuron

technical field

The invention relates to the synthesis of organic compounds, in particular to a preparation method of methyldisulfuron.

Background technique

Methyldisulfuron, also known as Methylsulfuron, chemical name 2-[(4,6-dimethoxypyrimidine 2-aminocarbonyl)aminosulfonyl]-a-(methylsulfonylamino)p-toluic acid Methyl ester is a new type of sulfonylurea herbicide developed by Bayer, Germany in 2002. Regarding sulfonylurea herbicides, it is the largest class of herbicides in the world. It mainly acts by inhibiting acetolactate synthase. , Weed roots and leaves absorb, conduct in the plant body, thereby prompting weeds to stop growing to achieve the effect of weeding. The agent has good control effect on some broadleaf weeds such as annual grass weeds in winter wheat, spring wheat and chickweed, and the demand for herbicides in my country is on the rise.

At present, the common synthetic method of methyldisulfuron on the market is through 4,6-dimethoxy-2-(phenoxycarbonyl)aminopyrimidine and 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzene Synthesis of two key intermediates of sulfonamide, in which the former intermediate has been industrialized and easily available in the market, so how to conveniently and effectively synthesize methyl 4-(methylsulfonylaminomethyl)2-kryptonsulfonylbenzoate this Key intermediates are the top priority.

(1) The relatively early method for synthesizing this key intermediate is the 1-tert-butylsulfonamide debutanation method. Patent DE4335297 takes 5-methyl-2-methoxycarbonylbenzenesulfonyl chloride as the starting material, first conducts amidation reaction, then NBS bromination, azide, Pd/C catalytic hydrogenation, and then methanesulfonylation to obtain Normalized tert-butyl-2-methoxycarbonyl-5-methanesulfonamide methylbenzenesulfonamide, and finally demethylated under the condition of trifluoroformic acid to obtain the target intermediate. The acidity of trifluoroformic acid is strong, and it is easy to corrode the production equipment , and the raw materials of this route are not easy to obtain, and the operation is relatively complicated at the same time, and the use of sodium azide in industrial production increases the risk of experiments, which is not conducive to industrial production.

(2) in order to find a relatively convenient synthetic method, Ma Changpeng et al. have improved its synthetic route. Patent CN103755603A takes p-toluene cyanide as a starting material, first reacts with chlorosulfonic acid, obtains sulfonyl chloride and conducts amination, Then it is oxidized under the action of potassium dichromate and concentrated acid, followed by reduction of palladium on carbon, methanesulfonylation, and methanol reflux to obtain the target intermediate. But potassium dichromate is easy to cause environmental pollution problems.

(3) at present, the most widely used is still Bayer patent, US6538150 first takes 4-cyano-2-nitrobenzoate as starting material, uses palladium hydroxide as catalyst, through reductive hydrogenation, methanesulfonyl chloride methanesulfonate Acylation and then diazotization reaction are carried out to obtain key intermediates, but in this route, precious metals are selected for reduction and hydrogenation, which is expensive, and the catalyst cannot be recycled, which limits industrial production.

SUMMARY OF THE INVENTION

Objective: The present invention provides a preparation method of methyldisulfuron, which has the advantages of simple operation, mild conditions and high yield.

Technical scheme: in order to solve the above-mentioned technical problems, the technical scheme adopted in the present invention is:

The present invention selects nickel to replace the use of precious metal palladium, which greatly reduces the production cost, and one step mainly uses benzyl mercaptan to directly undergo nucleophilic substitution reaction, so as to avoid production safety risks and reduce the generation of high COD wastewater.

A preparation method of methyldisulfuron, comprising:

Using methyl 4-cyano-2-nitrobenzoate as the starting material, it undergoes a nucleophilic substitution reaction with benzylthiol under alkaline conditions to obtain methyl 2-(benzylthio)-4-cyanobenzoate ester (compound 2);

Methyl 2-(benzylthio)-4-cyanobenzoate (compound ₂ ) undergoes a reduction reaction under the condition of H and Raney nickel as reducing agents to obtain 4-(aminomethyl)-2-(benzyl) thio) methyl benzoate (compound 3);

Methanesulfonyl chloride was added dropwise to methyl 4-(aminomethyl)-2-(benzylthio)benzoate (compound 3), and the reaction gave 2-(benzylthio)-4-(methylsulfonylaminomethyl) base) methyl benzoate (compound 4);

Methyl 2-(benzylthio)-4-(methylsulfonylaminomethyl)benzoate (compound 4) was chlorinated with chlorine and then aminated with ammonia to give 2-methoxycarbonyl-5-methanesulfonamide Methylbenzenesulfonamide (Compound 5);

Finally, 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide (compound 5) undergoes a coupling reaction with 4,6-dimethoxy-2-(phenoxycarbonyl)aminopyrimidine to obtain the target product methyl basesulfuron.

Specifically include the following steps:

Step 1) Using methyl 4-cyano-2-nitrobenzoate as a starting material, react with benzyl mercaptan under alkaline conditions to obtain methyl 2-(benzylthio)-4-cyanobenzoate (Compound 2), the reaction formula is as follows:

Step 2) 2-(benzylthio)-4-cyanomethyl benzoate (compound ₂ ) undergoes a reduction reaction under the condition that H and the reducing agent are Raney nickel to obtain 4-(aminomethyl)-2 -(benzylthio) methyl benzoate (compound 3), reaction formula:

Step 3) Add methanesulfonyl chloride dropwise to the mixture of methyl 4-(aminomethyl)-2-(benzylthio)benzoate (compound 3), acid binding agent and reaction solvent, and react to obtain 2-(benzylthio) base)-4-(methylsulfonamidomethyl) benzoic acid methyl ester (compound 4), reaction formula:

Step 4) Methyl 2-(benzylthio)-4-(methylsulfonamidomethyl)benzoate (compound 4) is chlorinated to obtain sulfonyl chloride under chlorine gas condition, and then passed into ammonia gas for amination to obtain 2 -Methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide (compound 5), reaction formula:

(3) Step 5) 2-Methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide (compound 5) and 2-amino-4,6-dimethylpyrimidine obtain methyldisulfonic acid under the condition of DBU Long (compound 6), reaction formula:

In step 1), the molar ratio of benzyl mercaptan to methyl 4-cyano-2-nitrobenzoate is 1 to 4; the reaction solvent is preferably DMF; by dropwise addition of sodium hydroxide solution or potassium hydroxide solution. Provide alkaline conditions, preferably potassium hydroxide solution, the concentration of potassium hydroxide solution is selected as 10～20%, and the molar ratio of potassium hydroxide and 4-cyano-2-nitrobenzoic acid methyl ester is 1～2 .

More preferably, the molar ratio of benzyl mercaptan and methyl 4-cyano-2-nitrobenzoate is preferably 1.16:1, and methyl 4-cyano-2-nitrobenzoate and benzyl mercaptan are dissolved in DMF. In, slowly drip the potassium hydroxide solution that concentration is 19% at 0 ℃, and potassium hydroxide and 4-cyano-2-nitrobenzoic acid methyl ester feed amount is preferably 1.9, after dripping, the room temperature reaction time is preferably After half an hour, the reaction was completed, poured into ice water and suction filtered to obtain methyl 2-(benzylthio)-4-cyanobenzoate (compound 2).

In step 2), the reducing agent is selected as Raney nickel, and the feeding amount of Raney nickel is 20% to 80% of the quality of methyl 2-(benzylthio)-4-cyanobenzoate (compound 2), and the reaction is performed. The solvent is methanol to be saturated with ammonia gas, the hydrogen pressure is 0.1-5 MPa, the reaction temperature is 10-30 DEG C, and the reaction time is 2-5 hours.

More preferably, use methyl 2-(benzylthio)-4-cyanobenzoate (compound 2) as raw material, add Raney nickel, and the amount of Raney nickel used is preferably 2-(benzylthio)- 60% of the mass of methyl 4-cyanobenzoate (compound 2), the reaction solvent is the methanol fed with ammonia to saturated, and the hydrogen pressure is 3MPa; the reaction temperature is preferably 25 ° C, the reaction time is preferably 3 hours, stop After reaction and further purification, methyl 4-(aminomethyl)-2-(benzylthio)benzoate (compound 3) was obtained.

In step 3), the reaction solvent is dichloromethane, the acid binding agent can be selected from pyridine or triethylamine, and the amount of the acid binding agent added is the same as 4-(aminomethyl)-2-(benzylthio) methyl benzoate ( The molar ratio of compound 3) is 1 to 2; the method for adding methanesulfonyl chloride is dropwise addition at low temperature, and the temperature is 0 to 10° C. After the dropwise addition, the reaction at room temperature is 1 to 4 hours. The molar ratio of methyl)-2-(benzylthio)benzoate (compound 3) is 1-2.

More preferably, first dissolving 4-(aminomethyl)-2-(benzylthio) methyl benzoate (compound 3) and an acid binding agent in dichloromethane, the acid binding agent is preferably triethylamine, The molar ratio of triethylamine to 4-(aminomethyl)-2-(benzylthio) methyl benzoate (compound 3) is preferably 1.2, and methanesulfonyl chloride is slowly added dropwise under ice bath, and methanesulfonyl chloride and 4 The feeding molar ratio of -(aminomethyl)-2-(benzylthio)benzoic acid methyl ester (compound 3) is preferably 1.5. After the completion of the dropwise addition, the reaction time at room temperature is preferably 1 hour, the reaction is stopped and purified to obtain methyl 2-(benzylthio)-4-(methylsulfonamidomethyl)benzoate (compound 4).

In step 4), first replace the benzylthio group as a sulfonyl chloride group and select a mixed solution of acetic acid and water as a reaction solvent, wherein the volume ratio of acetic acid and water is 3 to 8; chlorine is introduced at low temperature, and the temperature is 0 ～10°C; then the reaction solvent for the amination is tetrahydrofuran, and ammonia gas is introduced at low temperature, and the temperature is 0～10°C.

More preferably, the methyl 2-(benzylthio)-4-(methylsulfonamidomethyl)benzoate (compound 4) is mixed with acetic acid and water, and the ratio of acetic acid and water is preferably 5:1, Chlorine gas was introduced under ice bath, and the amount of chlorine gas introduced was the solid in the reaction system and stopped after 10 minutes. After the reaction was stopped, the mixture was extracted with ethyl acetate. The organic layer was taken and spin-dried. Purification gave 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide (compound 5).

In step 5), the molar ratio of 2-amino-4,6-methylpyrimidine and 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide is 1-2; the reaction solvent is acetonitrile; 2-Amino-4,6-methylpyrimidine and 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide were dissolved in acetonitrile, and DBU was added dropwise in an ice bath at 0-10°C; The molar ratio of 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide is 1-2, and the reaction is carried out at room temperature for 1-2 hours after the dropwise addition.

More preferably, 2-methoxycarbonyl-5-methanesulfonamidomethylbenzenesulfonamide (compound 5) and 2-amino-4,6-dimethylpyrimidine are first dissolved in acetonitrile, 2-methoxy The molar ratio of carbonyl-5-methanesulfonylaminomethylbenzenesulfonamide (compound 5) and 2-amino-4,6-dimethylpyrimidine is preferably 1.2, and DBU, DBU and 2-methyl pyrimidine are slowly added dropwise at 0°C The molar ratio of oxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide (compound 5) is preferably 1.1, after the dropwise addition, stirring at room temperature for 2 hours, stopping the reaction, and purifying to obtain the final product, methyldisulfuron .

Beneficial effects: the preparation method of methyldisulfuron provided by the present invention, the synthetic route of the present invention is compared with the route for preparing methyldisulfuron provided by the Bayer patent, and the reaction conditions of the route are first changed, and the operation is convenient. The yield is high. In the first step, we mainly use the starting material to have a direct nucleophilic substitution reaction with benzyl mercaptan to avoid production safety risks and reduce the generation of high COD wastewater. The reducing agent used in the reductive hydrogenation step of the route is Raney nickel, which is relatively cheap and reduces the cost of industrial production; the third step is methanesulfonyl chloride, which is environmentally friendly and produces no waste; the fourth step uses acetic acid It is mixed with water as a solvent, and chlorine gas is introduced, and then ammonia gas is introduced for ammoniation. For industrial production, the cost is very low, and there is no dangerous operation.

Detailed ways

In order to further illustrate the present invention, a series of examples are given below, which are purely illustrative, and are only used to specifically describe the present invention, and should not be construed as limiting the present invention.

The general synthetic route of methyldisulfuron (compound 6) is:

Example 1

1) Preparation of methyl 2-(benzylthio)-4-cyanobenzoate (compound 2)

1 g of methyl 4-cyano-2-nitrobenzoate, 700 mg of benzyl mercaptan and 10 ml of DMF were added to a 50 mL flask, and the resulting solution was hydrated and cooled to 0°C. An aqueous potassium hydroxide solution was prepared by dissolving 520 mg of potassium hydroxide in 2.2 ml of H ₂ O, and the potassium hydroxide solution was slowly added dropwise to the above solution under an ice bath. 30 minutes after the completion of the dropwise addition at room temperature, the reaction was completed, the mixture after the reaction was poured into ice water, and then suction filtered to obtain compound 2 as a yellow solid with a yield of 80.1%.

The product data are: ¹ H NMR (400MHz, Chloroform-d) δ 8.01 (d, J=8.0 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.40 (dt, J=7.9, 1.4 Hz) , 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 methanol until it was saturated. 1 g of methyl 2-(benzylthio)-4-cyanobenzoate, (600 mg, 60 wt%) Raney nickel and 30 mL of methanol were added to the autoclave. Under the hydrogen pressure of 3MPa, the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated, the residue was washed with water, extracted with ethyl acetate, and the organic layer was taken and distilled under reduced pressure to obtain compound 3 with a yield of 72.6%.

The product data are: ¹ H NMR(600MHz, Chloroform-d)δ7.86(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=8.0 Hz, 1H), 4.12 (s, 2H), 3.82 (s, 3H), 3.79 (s, 2H).

3) Preparation of methyl 2-(benzylthio)-4-(methylsulfonamidomethyl)benzoate (compound 4)

A 25ml round bottom flask was charged with 1g of methyl 4-(aminomethyl)-2-(benzylthio)benzoate, 0.56ml of triethylamine, 10ml of dichloromethane, and the resulting solution was cooled to 0°C and added to 0.65 ml 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, washed with NaHCO ₃ solution, extracted with ethyl acetate and purified by column chromatography to obtain compound 4 in a yield of 78.6%.

Product data are: ¹ H NMR (600MHz, Chloroform-d) δ 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-methanesulfonylaminomethylbenzenesulfonamide (compound 5)

Add 1g of 2-(benzylthio)-4-(methylsulfonamidomethyl)benzoic acid methyl ester, 6ml of acetic acid and 1.2ml of water to a 25ml round-bottomed flask, and pass chlorine gas under ice bath until the reaction system The solid disappeared and the reaction was stopped. Extract with ethyl acetate, combine the organic phases, and concentrate the organic phases under reduced pressure without further purification to obtain a crude intermediate compound, methyl 2-(chlorosulfonyl)-4-(methylsulfonamidomethyl)benzoate. The intermediate compound 2-(chlorosulfonyl)-4-(methylsulfonamidomethyl)benzoate and 10ml of tetrahydrofuran were added to a 25ml round-bottomed flask, and ammonia gas was introduced into it under an ice bath. The reaction was completed in 10 minutes and evaporated. solvent to give a white solid washed with methanol and water to give compound 5 in 72.4% yield.

The product data are: ¹ H NMR(400MHz, Acetone-d6)δ8.08-8.05(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 methyldisulfuron (compound 6)

Dissolve 1g of 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide and 1.02g of 4,6-dimethoxy-2-(phenoxycarbonyl)aminopyrimidine in 10ml of acetonitrile, and cool in an ice bath to 0 °C and slowly add 520 mg DBU dropwise, after the addition is completed, stir at room temperature for 1 hour, the reaction is completed, spin dry the solvent, add 7 ml of 2N HCl to the residue, a small amount of methanol, a large amount of solid is precipitated, and suction filtration to obtain compound 6, which is produced. rate 83.6%.

The product data are: ¹ H NMR(400MHz, Chloroform-d)δ12.66(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)

5 g of methyl 4-cyano-2-nitrobenzoate, 3.5 g of benzyl mercaptan and 45 ml of DMF were added to a 250 mL flask, and the resulting solution was hydrated and cooled to 0°C. An aqueous potassium hydroxide solution was prepared by dissolving 2.6 g of potassium hydroxide in 11 ml of H ₂ O, and the potassium hydroxide solution was slowly added dropwise to the above solution under an ice bath. After the dropwise addition, the reaction was carried out at room temperature for 30 minutes, and the reaction was completed. The mixture after the reaction was poured into ice water, and then suction filtered to obtain compound 2 as a yellow solid with a yield of more than 80%.

The product data are: ¹ H NMR (400MHz, Chloroform-d) δ 8.01 (d, J=8.0 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.40 (dt, J=7.9, 1.4 Hz) , 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 methanol until it was saturated. 5 g of methyl 2-(benzylthio)-4-cyanobenzoate, (1.5 g, 60 wt%) Raney nickel and 100 mL of methanol were added to the autoclave. Under the hydrogen pressure of 3MPa, the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated, washed with water, extracted with ethyl acetate, and the organic layer was distilled under reduced pressure to obtain compound 3 with a yield of over 70%.

The product data are: ¹ H NMR(600MHz, Chloroform-d)δ7.86(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=8.0 Hz, 1H), 4.12 (s, 2H), 3.82 (s, 3H), 3.79 (s, 2H).

3) Preparation of methyl 2-(benzylthio)-4-(methylsulfonamidomethyl)benzoate (compound 4)

In a 100ml round-bottomed flask, 5g of methyl 4-(aminomethyl)-2-(benzylthio)benzoate, 2.8ml of triethylamine, 35ml of dichloromethane were added, and the resulting solution was cooled to 0°C and added to 3.4 ml 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, washed with NaHCO ₃ solution, extracted with ethyl acetate and purified by column chromatography to obtain compound 4 with a yield of over 70%.

Product data are: ¹ H NMR (600MHz, Chloroform-d) δ 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-methanesulfonylaminomethylbenzenesulfonamide (compound 5)

Add 5g of methyl 2-(benzylthio)-4-(methylsulfonamidomethyl)benzoate, 30ml of acetic acid and 6ml of water into a 100ml round-bottomed flask, and pass chlorine gas at 0 to 10°C until the reaction system The solids disappeared and the reaction was stopped. Extract with ethyl acetate, combine the organic phases, and concentrate the organic phases under reduced pressure without further purification to obtain a crude intermediate compound, methyl 2-(chlorosulfonyl)-4-(methylsulfonamidomethyl)benzoate. The intermediate compound, methyl 2-(chlorosulfonyl)-4-(methylsulfonamidomethyl)benzoate, and 35 ml of tetrahydrofuran were added to a 100 ml round-bottomed flask, and ammonia gas was introduced into it under an ice bath, and the solvent was evaporated to obtain a white solid After washing with methanol and water, compound 5 was obtained in a yield of over 60%.

The product data are: ¹ H NMR(400MHz, Acetone-d6)δ8.08-8.05(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 methyldisulfuron (compound 6)

Dissolve 5g 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide, 5.2g 4,6-dimethoxy-2-(phenoxycarbonyl)aminopyrimidine in 40ml acetonitrile, cool in ice bath To 0 ° C and slowly add 2.6g DBU dropwise, after the completion of the dropwise stirring at room temperature for 1 hour, the reaction is completed, spin dry the solvent, add 35ml of 2N HCl to the residue, a small amount of methanol, a large amount of solid precipitation, suction filtration to obtain compound 6, The yield is over 80%.

The product data are: ¹ H NMR(400MHz, Chloroform-d)δ12.66(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 is only the preferred embodiment of the present invention, it should be pointed out: for those skilled in the art, under the premise of not departing from the principle of the present invention, several improvements and modifications can also be made, and these improvements and modifications are also It should be regarded as the protection scope of the present invention.

Claims (15)

1. a preparation method of methyldisulfuron, is characterized in that, comprises: Using methyl 4-cyano-2-nitrobenzoate as the starting material, it undergoes a nucleophilic substitution reaction with benzylthiol under alkaline conditions to obtain methyl 2-(benzylthio)-4-cyanobenzoate ester; Methyl 2-(benzylthio)-4-cyanobenzoate undergoes a reduction reaction under the condition of H ₂ and Raney nickel as reducing agent to obtain 4-(aminomethyl)-2-(benzylthio)benzene methyl formate (compound 3); Methanesulfonyl chloride was added dropwise to methyl 4-(aminomethyl)-2-(benzylthio)benzoate to obtain 2-(benzylthio)-4-(methylsulfonamidomethyl)benzoic acid. methyl ester; 2-(Benzylthio)-4-(methylsulfonamidomethyl)benzoic acid methyl ester is chlorinated with chlorine gas, and then ammoniated with ammonia gas to obtain 2-methoxycarbonyl-5-methanesulfonamidomethylbenzenesulfonate amide; Finally, 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide is coupled with 4,6-dimethoxy-2-(phenoxycarbonyl)aminopyrimidine to obtain the target product, methyldisulfuron . 2. the preparation method of methyldisulfuron according to claim 1, is characterized in that, specifically comprises the following steps: Step 1) Using methyl 4-cyano-2-nitrobenzoate as a starting material, react with benzyl mercaptan under alkaline conditions to obtain methyl 2-(benzylthio)-4-cyanobenzoate , namely compound 2, the reaction formula is as follows:

Step ₂ ) 2-(benzylthio)-4-cyanobenzoic acid methyl ester undergoes a reduction reaction under the condition that H and the reducing agent are Raney nickel to obtain 4-(aminomethyl)-2-(benzylthio) base) methyl benzoate, namely compound 3, reaction formula:

Step 3) Add methanesulfonyl chloride dropwise to the mixture of methyl 4-(aminomethyl)-2-(benzylthio)benzoate, acid binding agent and reaction solvent, and react to obtain 2-(benzylthio)-4 -(Methylsulfonamidomethyl)benzoic acid methyl ester, namely compound 4, reaction formula:

Step 4) Methyl 2-(benzylthio)-4-(methylsulfonamidomethyl)benzoate is chlorinated under chlorine gas to obtain sulfonyl chloride, and then ammoniated with ammonia to obtain 2-methoxycarbonyl -5-Methanesulfonamidomethylbenzenesulfonamide, namely compound 5, reaction formula:

Step 5) 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide and 2-amino-4,6-dimethylpyrimidine obtain methyldisulfuron-methyl under the condition of DBU, that is, compound 6, react Mode:

3. the preparation method of methyldisulfuron according to claim 2, is characterized in that, in step 1) in, the molar ratio of benzyl mercaptan and 4-cyano-2-nitrobenzoic acid methyl ester is 1～ 4. 4. the preparation method of methyldisulfuron according to claim 2, is characterized in that, in step 1), reaction solvent is DMF. 5. The preparation method of methyldisulfuron according to claim 2, characterized in that, in step 1), alkaline conditions are provided by dropwise addition of sodium hydroxide solution or potassium hydroxide solution. 6. the preparation method of methyldisulfuron according to claim 5, is characterized in that, the alkaline condition adopts potassium hydroxide solution, and the concentration of potassium hydroxide solution is selected as 10～20%, potassium hydroxide and 4-cyanide The molar ratio of methyl-2-nitrobenzoate is 1-2. 7. the preparation method of methyldisulfuron according to claim 2, is characterized in that, in step 2) in, the charging capacity of Raney nickel is 2-(benzylthio)-4-cyanobenzoic acid methyl ester ( 20% to 80% of the mass of compound 2). 8. the preparation method of methyldisulfuron according to claim 2, it is characterised in that in step 2), the reaction solvent is to feed ammonia to saturated methanol, the hydrogen pressure is 0.1～5MPa, and the reaction temperature is 10～ 30 ° C, the reaction time is 2 to 5 hours. 9. The preparation method of methyldisulfuron according to claim 2, characterized in that, in step 3), the reaction solvent is dichloromethane. 10. the preparation method of methyldisulfuron according to claim 2, is characterized in that, in step 3), acid binding agent selects pyridine or triethylamine, and the amount that acid binding agent adds and 4-(aminomethyl) The molar ratio of -2-(benzylthio) benzoic acid methyl ester is 1-2. 11. The preparation method of methyldisulfuron according to claim 2, characterized in that, in step 3), the method for adding methanesulfonyl chloride is dropwise addition at low temperature, the temperature is 0～10°C, and the reaction is performed at room temperature after the dropwise addition is completed. In 1-4 hours, the molar ratio of methanesulfonyl chloride to methyl 4-(aminomethyl)-2-(benzylthio)benzoate is 1-2. 12. The preparation method of methyldisulfuron-methyl according to claim 2, is characterized in that, in step 4), first replace benzylthio group as sulfonyl chloride group and select the mixed solution of acetic acid and water as reaction solvent, wherein, acetic acid The volume ratio to water is 3 to 8; chlorine gas is introduced at low temperature, and the temperature is 0 to 10 °C. 13. The preparation method of methyldisulfuron-methyl according to claim 2, characterized in that, in step 4), the reaction solvent of the amination is tetrahydrofuran, and ammonia gas is introduced at low temperature, and the temperature is 0～10°C. 14. The preparation method of methyldisulfuron according to claim 2, wherein in step 5), 2-amino-4,6-methylpyrimidine and 2-methoxycarbonyl-5-methanesulfonyl The molar ratio of aminomethylbenzenesulfonamide is 1-2; the reaction solvent is acetonitrile. 15. The preparation method of methyldisulfuron-methyl according to claim 14, characterized in that, 2-amino-4,6-methylpyrimidine and 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzene The sulfonamide was dissolved in acetonitrile, and DBU was added dropwise in an ice bath at 0-10°C; The molar ratio of DBU to 2-methoxycarbonyl-5-methanesulfonylaminomethylbenzenesulfonamide is 1-2, and the reaction is performed at room temperature for 1-2 hours after the dropwise addition.