Preparation method of saflufenacil intermediate

Abstract

The present invention relates to the field of pesticides, and discloses a saflufenacil intermediate preparation method, which comprises: 1) carrying out a nitration reaction on a compound represented by a formula III, sulfuric acid and nitric acid to obtain a nitration product; 2) subjecting the nitration product to a hydrolysis reaction to obtain a compound of formula V; (3) carrying out hydrogenation reaction on the compound shown in the formula V to obtain a compound shown in a formula VI; (4) carrying out esterification reaction on the compound shown in the formula VI and chloroformate to obtain a compound shown in a formula VII; and (5) carrying out sulfonylation reaction on the compound as shown in the formula VII and N-methyl isopropylamine sulfonyl chloride to obtain a compound as shown in a formula VIII. The invention provides the novel preparation method of the saflufenacil intermediate, and the method is lower in cost, lower in three wastes and simpler to operate.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pesticides, in particular to a preparation method of a foramsulfuron intermediate. BACKGROUND

[0002] Foramsulfuron is a new urea herbicide, which belongs to the class of protoporphyrinogen oxidase (PPO) inhibitors. It can be used in more than 30 crops and can control more than 100 broadleaf weeds. Its high weed control effect and crop selectivity are outstanding among existing PPO inhibitor herbicides. It has great potential in the herbicide market for no-tillage, non-cultivated land, orchards, legumes and wheat crops.

[0003] The synthesis method of foramsulfuron was first recorded in WO01 / 83459. The application discloses an N,N-dimethyl formyl chloride method, which uses two expensive raw materials, N,N-dimethyl formyl chloride and chlorosulfonyl isocyanate. At the same time, the route is tedious, the yield is low, and it is not suitable for large-scale production.

[0004]

[0005] The mainstream route of foramsulfuron so far is to use 2-chloro-4-fluorobenzoic acid as raw material, and to synthesize through nitration, sulfonylation, hydrogenation and ring closure. This route has low yield, harsh conditions and high production cost.

[0006]

[0007] CN113185467A discloses a continuous chlorination method, which uses chlorine gas to continuously chlorinate three times to obtain a trichloromethylbenzene intermediate, and then performs subsequent sulfonylation to obtain foramsulfuron. This route is dangerous, harsh and not easy to produce on a large scale.

[0008]

[0009] CN113979953A discloses a synthesis method of a foramsulfuron intermediate, which uses 3-amino-4-fluorobenzonitrile as raw material, and performs acylation, chlorination, sulfonylation and ring closure reaction to obtain the foramsulfuron intermediate.

[0010]

[0011] In summary, the existing production process of foramsulfuron intermediate compound has the disadvantages of high cost, high three wastes, high risk, etc. In order to improve market competitiveness, a process route with lower cost, lower three wastes and simpler operation needs to be found. SUMMARY

[0012] The present application aims at overcoming the problems of high cost, high waste, high risk and the like in the prior art, and provides a new preparation method of a pyroxsulam intermediate, which is more low-cost, lower in waste and simpler in operation.

[0013] To achieve the above-mentioned object, the present application provides a preparation method of a pyroxsulam intermediate, wherein the method comprises the following steps,

[0014] 1) nitration reaction of a compound shown in formula III with sulfuric acid and nitric acid to obtain a nitration product containing a compound shown in formula IV;

[0015] 2) hydrolysis reaction of the nitration product obtained in step 1) to obtain a compound shown in formula V;

[0016] 3) hydrogenation reaction of the compound shown in formula V to obtain a compound shown in formula VI;

[0017] 4) esterification reaction of the compound shown in formula VI with chloroformate to obtain a compound shown in formula VII;

[0018] 5) sulfonylation reaction of the compound shown in formula VII with N-methyl isopropyl amine sulfonyl chloride to obtain a compound shown in formula VIII,

[0019]

[0020] In formula VII and formula VIII, R is an alkyl group with 1-6 carbon atoms.

[0021] Preferably, the concentration of the sulfuric acid is 80% by weight or more, preferably 80-98% by weight.

[0022] Preferably, the molar ratio of the compound shown in formula III to the sulfuric acid is 1:1-15, preferably 1:2-4.

[0023] Preferably, the concentration of the nitric acid is 65% by weight or more, preferably 65-98% by weight.

[0024] Preferably, the molar ratio of the compound shown in formula III to the nitric acid is 1:1.01-1.1, preferably 1:1.03-1.05.

[0025] Preferably, the conditions of the nitration reaction include: the reaction temperature is 10-100℃, preferably 30-40℃; the reaction time is 0.5-10h, preferably 0.5-2h.

[0026] Preferably, in the hydrolysis reaction, the molar ratio of the compound of the structure shown in formula IV to additional water is 1:0-10, preferably no additional water is added.

[0027] Preferably, the conditions of the hydrolysis reaction include: the reaction temperature is 90-180℃, preferably 100-110℃; the reaction time is 1-10h, preferably 1-2h.

[0028] Preferably, the hydrogenation reaction is carried out in the presence of a first solvent, and the first solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, propanol, butanol, toluene and chlorobenzene, preferably methanol.

[0029] Preferably, the hydrogenation reaction is carried out in the presence of a first catalyst, and the first catalyst is one or more of Raney nickel, palladium on carbon and platinum on carbon, preferably Raney nickel.

[0030] Preferably, in the hydrogenation reaction, the molar mass ratio of the compound of the structure shown in formula V to the catalyst is 1 mol:(10-20g), preferably 1 mol:(12-15g).

[0031] Preferably, in the hydrogenation reaction, the reaction pressure is 0.5-2MPa, preferably 1-1.3Mpa.

[0032] Preferably, the conditions of the hydrogenation reaction include: the reaction temperature is 20-70℃, preferably 55-60℃; the reaction time is 2-10h, preferably 5-6h.

[0033] Preferably, in the esterification reaction, the chloroformate is one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate, butyl chloroformate, pentyl chloroformate and hexyl chloroformate, preferably methyl chloroformate.

[0034] Preferably, the molar ratio of the compound of the structure shown in compound VI to the chloroformate is 1:1-2, preferably 1:1.2-1.5.

[0035] Preferably, the esterification reaction is carried out in the presence of a second solvent, and the second solvent is one or more of dichloromethane, 1,2-dichloroethane, toluene, xylene, trifluorotoluene and chlorobenzene, preferably 1,2-dichloroethane.

[0036] Preferably, the conditions of the esterification reaction include: the reaction temperature is 40-120℃, preferably 70-80℃; the reaction time is 1-10h, preferably 3-4h.

[0037] Preferably, in the sulfonylation reaction, the molar ratio of the compound of the structure represented by compound VII to N-methylisopropylamine sulfuryl chloride is 1:1-2, preferably 1:1.2-1.4.

[0038] Preferably, the sulfonylation reaction is carried out in the presence of a third solvent, which is one or more of toluene, xylene, trifluorotoluene, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, preferably toluene.

[0039] Preferably, the sulfonylation reaction is carried out in the presence of a base, which is one or more of triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, preferably triethylamine.

[0040] Preferably, the molar ratio of the compound of the structure represented by compound VII to the base is 1:2-8, preferably 1:3-4.

[0041] Preferably, the conditions of the sulfonylation reaction include that the reaction temperature is 50-140°C, preferably 100-110°C; and the reaction time is 3-10h, preferably 5-6h.

[0042] Preferably, the method further comprises the step of fluorinating the compound of the structure represented by formula II to obtain the compound of the structure represented by formula III.

[0043]

[0044] Preferably, in the fluorination reaction, the fluorinating agent is potassium fluoride and / or sodium fluoride, preferably potassium fluoride.

[0045] Preferably, the fluorination reaction is carried out in the presence of a second catalyst, which is one or more of tetraphenylphosphonium bromide, tetrabutylphosphonium bromide and tetraethylphosphonium bromide, preferably tetraphenylphosphonium bromide.

[0046] Preferably, in the fluorination reaction, the molar ratio of the compound of the structure represented by formula II to the second catalyst is 1:0.01-0.1, preferably 1:0.03-0.05.

[0047] Preferably, in the fluorination reaction, the molar ratio of the compound of the structure represented by formula II to the fluorinating agent is 1:1-2, preferably 1:1.1-1.3.

[0048] Preferably, the fluorination reaction is carried out in the presence of a fourth solvent, which is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane and diphenyl ether, preferably dimethylsulfoxide.

[0049] Preferably, the conditions of the fluorination reaction include: the reaction temperature is 120-200℃, preferably 130-140℃; the reaction time is 1-10h, preferably 2-3h.

[0050] Preferably, the method further comprises the step of cyanating the compound of the structure shown in Formula I to obtain the compound of the structure shown in Formula II.

[0051]

[0052] Preferably, in the cyanation reaction, the cyanating agent is one or more of cuprous cyanide, sodium cyanide and potassium cyanide, preferably cuprous cyanide.

[0053] Preferably, in the cyanation reaction, the molar ratio of the compound of the structure shown in Formula I to the cyanating agent is 1:1-2, preferably 1:1.3-1.5.

[0054] Preferably, the cyanation reaction is carried out in the presence of a fifth solvent, which is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane and diphenyl ether, preferably dimethyl sulfoxide.

[0055] Preferably, the conditions of the cyanation reaction include: the reaction temperature is 140-220℃, preferably 180-190℃; the reaction time is 5-12h, preferably 7-8h.

[0056] Preferably, in Formula VII and Formula VIII, R is an alkyl group with 1-3 carbon atoms.

[0057] Preferably, in Formula VII and Formula VIII, R is a methyl group.

[0058] Compared with the prior art, the present application has the following beneficial effects.

[0059] 1) Avoid using expensive 2-chloro-4-fluorobenzoic acid, greatly reducing the cost of raw materials;

[0060] 2) In the synthesis route of the present application, the regioselectivity of the nitration reaction is as high as more than 97%, compared with the regioselectivity of about 80% of the nitration reaction of 2-chloro-4-fluorobenzoic acid, which can effectively reduce the generation of by-products;

[0061] 3) The reaction post-treatment operation is simple, the three wastes are less, the yield is high, and it is more suitable for industrialized production. DETAILED DESCRIPTION

[0062] The endpoints of the ranges and any values disclosed herein are not limited to the precise values recited as the exact dimensions are not considered critical for the purposes of the application. The endpoints of the ranges and any values are provided as approximations only and are understood to encompass a range of values which are near the value recited in the endpoints. Any numerical value, however, can only be approximated because it is expected to vary at the least with time, the limitations of being measured with testing equipment, and variations in temperatures and other known or expected deviations or variations in manufacturing a part or for or a device. Unless otherwise stated, all ranges include all values between the upper and lower limit of that range. In general, the application encompasses all ranges and values less than or greater than those stated.

[0063] The present application provides a method for preparing a mesosulfuron intermediate, wherein the method comprises the steps of,

[0064] 1) a step of subjecting a compound having a structure represented by Formula III to a nitration reaction with sulfuric acid and nitric acid to obtain a nitration product containing a compound having a structure represented by Formula IV;

[0065] 2) a step of subjecting the nitration product obtained in step 1) to a hydrolysis reaction to obtain a compound having a structure represented by Formula V;

[0066] 3) a step of subjecting the compound having a structure represented by Formula V to a hydrogenation reaction to obtain a compound having a structure represented by Formula VI;

[0067] 4) a step of subjecting the compound having a structure represented by Formula VI to an esterification reaction with chloroformate to obtain a compound having a structure represented by Formula VII;

[0068] 5) a step of subjecting the compound having a structure represented by Formula VII to a sulfonylation reaction with N-methylisopropylamine sulfonyl chloride to obtain a compound having a structure represented by Formula VIII,

[0069]

[0070] In Formulas VII and VIII, R is an alkyl group having 1 to 6 carbon atoms.

[0071] In the method for preparation according to the present application, preferably, R is an alkyl group having 1 to 3 carbon atoms.

[0072] As the alkyl group having 1 to 6 carbon atoms, it can be a straight chain alkyl group or a branched chain alkyl group, and preferably it is a straight chain alkyl group, and for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, or the like can be mentioned, among which, a methyl group, an ethyl group, or a propyl group is preferred, and a methyl group is more preferred.

[0073] The present application will be described in the following steps.

[0074] 1) Nitration reaction step

[0075] In the present application, a compound having a structure represented by Formula III is subjected to a nitration reaction with sulfuric acid and nitric acid to obtain a nitration product containing a compound having a structure represented by Formula IV.

[0076] According to the preparation method of the present application, by using 2-chloro-4-fluorobenzonitrile, the selectivity can be improved significantly, almost no 3-position mononitrated isomer is generated, no subsequent purification is needed, and the obtained product can be directly used in the next step of synthesis, thereby effectively saving a large amount of recrystallization solvent; and the two-step reaction can be realized in one pot without separation of the intermediate, the operation is simple, the conditions are mild, the yield is high, and the method is suitable for industrial production.

[0077] According to the preparation method of the present application, in step 1), the concentration of the sulfuric acid can be 80% by weight or more; preferably, in step 1), the concentration of the sulfuric acid is 80-98% by weight.

[0078] In a particularly preferred embodiment of the present application, the concentration of the sulfuric acid is 98% by weight.

[0079] According to the preparation method of the present application, the amount of the sulfuric acid can be selected according to the amount of 2-chloro-4-fluorobenzonitrile; preferably, the molar ratio of 2-chloro-4-fluorobenzonitrile to the sulfuric acid is 1:1-15; more preferably, the molar ratio of 2-chloro-4-fluorobenzonitrile to the sulfuric acid is 1:2-4.

[0080] As specific examples of the molar ratio of 2-chloro-4-fluorobenzonitrile to the sulfuric acid, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, and the range formed by any two of the above can be mentioned.

[0081] According to the preparation method of the present application, the concentration of the nitric acid can be 65% by weight or more; preferably, the concentration of the nitric acid is 65-98% by weight.

[0082] In a particularly preferred embodiment of the present application, the concentration of the nitric acid is 98% by weight.

[0083] According to the preparation method of the present application, the amount of the nitric acid can be selected according to the amount of 2-chloro-4-fluorobenzonitrile; preferably, the molar ratio of 2-chloro-4-fluorobenzonitrile to the nitric acid is 1:1.01-1.1, preferably 1:1.03-1.05.

[0084] In a particularly preferred embodiment of the present application, the molar ratio of 2-chloro-4-fluorobenzonitrile to the nitric acid is 1:1.03-1.05, thereby further improving the selectivity and the yield.

[0085] As specific examples of the molar ratio of 2-chloro-4-fluorobenzonitrile to the nitric acid, for example, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.1, and the like, and a range constituted by any two of the above can be given.

[0086] According to the preparation method of the present application, preferably, the conditions of the nitration reaction include that the reaction temperature is 10-100°C and the reaction time is 0.5-10h; more preferably, the conditions of the nitration reaction include that the reaction temperature is 35-40°C and the reaction time is 0.5-2h.

[0087] According to the method of the present application, after the completion of the nitration reaction, the nitration reaction product can be directly used for the hydrolysis reaction without treatment.

[0088] 2) Hydrolysis reaction step

[0089] In the present application, the nitration product obtained in step 1) is subjected to a hydrolysis reaction to obtain a compound of the structure shown in formula V.

[0090] According to the preparation method of the present application, the nitration product obtained in step 1) can be directly subjected to a hydrolysis reaction (without adding additional water), and the hydrolysis reaction can also be performed by additionally adding water as needed; specifically, the molar ratio of the compound of the structure shown in formula IV to the additional water is 1:0-10, and preferably no additional water is added.

[0091] As specific examples of the molar ratio of the compound of the structure shown in formula IV to the additional water, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, and the like, and a range constituted by any two of the above can be given.

[0092] According to the preparation method of the present application, preferably, the conditions of the hydrolysis reaction include that the reaction temperature is 90-180°C and the reaction time is 1-10h; more preferably, the conditions of the hydrolysis reaction include that the reaction temperature is 100-130°C and the reaction time is 1-2h; more preferably, the conditions of the hydrolysis reaction include that the reaction temperature is 100-110°C and the reaction time is 1-1.5h.

[0093] According to the preparation method of the present application, due to the good selectivity in the nitration reaction, almost no 3-position mononitration isomer is generated, and thus after the completion of the hydrolysis reaction, the reaction liquid is only contacted with water to precipitate the compound of the structure shown in formula V, which is simple in operation, mild in conditions, and high in yield, and is suitable for industrial production.

[0094] In a preferred embodiment of the present application, after the hydrolysis reaction is completed, the reaction solution is poured into water with stirring, and the solid is precipitated, separated, washed, and dried to obtain a compound of the structure shown in formula V with high purity. At this time, the amount of water used can be 0.5 to 1.2 times, preferably 0.55 to 1 times, and more preferably 0.6 to 0.8 times, the amount of the hydrolysis reaction product.

[0095] In a specific embodiment of the present application, the reaction solution can be slowly poured into crushed ice with stirring, and after the solid is precipitated, it is separated, washed, and dried.

[0096] 3) Hydrogenation reaction step

[0097] In the present application, a compound of the structure shown in formula V is subjected to a hydrogenation reaction to obtain a compound of the structure shown in formula VI.

[0098] According to the preparation method of the present application, in order to promote the reaction, preferably, the hydrogenation reaction is carried out in the presence of a first solvent, and as the first solvent, only a solvent that is inert to the reaction raw material and can dissolve the reaction raw material is required, and preferably, the first solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, propanol, butanol, toluene, and chlorobenzene, and more preferably, methanol.

[0099] In a particularly preferred embodiment of the present application, the first solvent is methanol, and by using methanol as the solvent, the yield, reaction selectivity, and reaction time can be improved.

[0100] In the present application, the amount of the first solvent can be selected according to the amount of the compound of the structure shown in formula V, for example, the amount of the first solvent is 3 to 10 times, preferably 5 to 6 times, the amount of the compound of the structure shown in formula V, for example, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, etc., and a range formed by any two of the above.

[0101] According to the preparation method of the present application, preferably, the hydrogenation reaction is carried out in the presence of a first catalyst, and the first catalyst is one or more of Raney nickel, palladium on carbon, and platinum on carbon, and more preferably, Raney nickel.

[0102] In a preferred embodiment of the present application, the first catalyst is Raney nickel, and by using Raney nickel, the side reaction of dehalogenation is less likely to occur, and the yield is higher.

[0103] According to the preparation method of the present application, preferably, in the hydrogenation reaction, the molar mass ratio of the compound of the structure shown in formula V to the catalyst is 1 mol:(10-20 g), and more preferably, 1 mol:(12-15 g).

[0104] According to the preparation method of the present application, preferably, the reaction pressure in the hydrogenation reaction is 0.5-2 MPa, more preferably 1-1.3 MPa. Here, the reaction pressure refers to the hydrogen pressure, which is in terms of gauge pressure.

[0105] According to the preparation method of the present application, preferably, the hydrogenation reaction conditions include that the reaction temperature is 20-70°C, more preferably 55-60°C. In addition, the reaction time can be as long as the reaction is completed, for example, the reaction can be stopped when the pressure is stable.

[0106] After the reaction is completed, the reaction solution can be refined by using conventional methods in the art. Preferably, the reaction solution is subjected to solid-liquid separation, the solvent is recovered from the liquid phase, and then the liquid phase is washed with water to obtain the compound of formula VI. At this time, the amount of water used is 2-3 times the mass of the compound of formula VI; the washing temperature can be 0-5°C.

[0107] In addition, the recovered catalyst after the solid-liquid separation of the reaction solution can be used in the synthesis of the next batch.

[0108] 4) Esterification reaction step

[0109] In the present application, the compound of formula VI is subjected to an esterification reaction with chloroformate to obtain the compound of formula VII.

[0110] According to the preparation method of the present application, in the esterification reaction, the chloroformate is preferably one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate, butyl chloroformate, pentyl chloroformate, and hexyl chloroformate, more preferably methyl chloroformate.

[0111] According to the preparation method of the present application, the amount of chloroformate used can be selected according to the amount of the compound of formula VI, preferably, the molar ratio of the compound of formula VI to chloroformate is 1:1-2, more preferably 1:1.2-1.5.

[0112] As specific examples of the molar ratio of the compound of formula VI to chloroformate, for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, and the range formed by any two of the above can be mentioned.

[0113] According to the production method of the present application, in order to promote the reaction, preferably, the esterification reaction is performed in the presence of a second solvent, and as the second solvent, only a solvent which is inert to the reaction raw materials and which can dissolve the reaction raw materials is necessary, and preferably, the second solvent is one or more of dichloromethane, 1,2-dichloroethane, toluene, xylene, trifluorotoluene, and chlorobenzene, and more preferably, the second solvent is 1,2-dichloroethane.

[0114] In a preferred embodiment of the present application, the second solvent is 1,2-dichloroethane, and by using 1,2-dichloroethane as the solvent, it is possible to further provide the yield and purity.

[0115] In the present application, the amount of the second solvent can be selected in accordance with the amount of the compound of the structure represented by Formula VI, and for example, the amount of the second solvent can be 3 to 10 times, preferably 5 to 6 times, the amount by weight of the compound of the structure represented by Formula VI, and for example, it can be 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, or the like, and a range formed by any two of the above.

[0116] According to the production method of the present application, preferably, the conditions of the esterification reaction include a reaction temperature of 40 to 120°C, and more preferably, 70 to 80°C, and a reaction time of 1 to 10 hours, and more preferably, 3 to 4 hours.

[0117] After the reaction, it is possible to perform purification by using a conventional method in the art, and preferably, the reaction solution is subjected to solvent recovery, and then washed with water to obtain the compound of the structure represented by Formula VII. At this time, the amount of water used is 1 to 2 times the mass. The temperature of the washing can be room temperature.

[0118] 5) Sulfurylation reaction step

[0119] In the present application, the compound of the structure represented by Formula VII is subjected to sulfurylation reaction with N-methylisopropylamine sulfonyl chloride to obtain the compound of the structure represented by Formula VIII.

[0120] According to the production method of the present application, preferably, in the sulfurylation reaction, the molar ratio of the compound of the structure represented by Formula VII to N-methylisopropylamine sulfonyl chloride is 1:1 to 2, and more preferably, 1:1.2 to 1.4.

[0121] As a specific example of the molar ratio of the compound of the structure represented by Formula VII to N-methylisopropylamine sulfonyl chloride, for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, or the like, and a range formed by any two of the above can be given.

[0122] According to the production method of the present application, in order to promote the reaction, preferably, the sulfonylation reaction is performed in the presence of a third solvent, and as the third solvent, only a solvent which is inert to the reaction raw materials and which can dissolve the reaction raw materials is necessary, and preferably, the third solvent is one or more of toluene, xylene, trifluorotoluene, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and more preferably, toluene.

[0123] In a preferred embodiment of the present application, the third solvent is toluene, and by using toluene as the solvent, the yield can be further improved and the reaction time can be shortened.

[0124] In the present application, the amount of the third solvent can be selected according to the amount of the compound of the structure represented by Formula VII, and for example, the amount of the third solvent is 3 to 10 times by weight, preferably 5 to 6 times by weight, of the compound of the structure represented by Formula VII, and for example, it can be 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, 9 parts by weight, 10 parts by weight, or the like, and a range formed by any two of the above.

[0125] According to the production method of the present application, preferably, the sulfonylation reaction is performed in the presence of an acid-binding agent, and the acid-binding agent is one or more of triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, and more preferably, triethylamine.

[0126] According to the production method of the present application, preferably, the molar ratio of the compound of the structure represented by Formula VII to the acid-binding agent is 1:2 to 8, and preferably 1:3 to 4.

[0127] As a specific example of the molar ratio of the compound of the structure represented by Formula VII to the acid-binding agent, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or the like, and a range formed by any two of the above can be given.

[0128] According to the production method of the present application, preferably, the conditions of the sulfonylation reaction include a reaction temperature of 50 to 140°C, and preferably 100 to 110°C, and a reaction time of 3 to 10 hours, and preferably 4 to 5 hours.

[0129] After the reaction is completed, purification can be performed by a conventional method in the art, and preferably, the reaction solution is subjected to solvent recovery, and then washed with water to obtain the compound of the structure represented by Formula VIII. At this time, the amount of water used is 2 to 3 times by mass.

[0130] 6) Cyanation step and fluorination step

[0131] In the present application, in order to further reduce the cost, the compound of the structure shown in formula I is used as the raw material, cyanide is used to obtain the compound of the structure shown in formula II, and fluorination is used to obtain the compound of the structure shown in formula III.

[0132]

[0133] Cyanide step

[0134] In the present application, the step of cyaniding the compound of the structure shown in formula I to obtain the compound of the structure shown in formula II is also included.

[0135] According to the preparation method of the present application, preferably, in the cyanide reaction, the cyanide reagent is one or more of cuprous cyanide, sodium cyanide and potassium cyanide, and more preferably cuprous cyanide.

[0136] According to the preparation method of the present application, preferably, in the cyanide reaction, the molar ratio of the compound of the structure shown in formula I to the cyanide reagent is 1:1-2, and more preferably 1:1.3-1.5.

[0137] As a specific example of the molar ratio of the compound of the structure shown in formula I to the cyanide reagent, for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, and the range formed by any two of the above can be mentioned.

[0138] According to the preparation method of the present application, in order to promote the reaction, preferably, the cyanide reaction is carried out in the presence of a fifth solvent, as long as the fifth solvent is inert to the raw materials of the reaction and can dissolve the raw materials of the reaction, and preferably the fifth solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane and diphenyl ether, and preferably dimethyl sulfoxide.

[0139] In the present application, the amount of the fifth solvent can be selected according to the amount of the compound of the structure shown in formula I, for example, the amount of the fifth solvent is 2-8 times the amount of the compound of the structure shown in formula I by weight, and preferably 2-3 times by weight, for example, 3 parts by weight, 4 parts by weight, 5 parts by weight, 6 parts by weight, 7 parts by weight, 8 parts by weight, and the range formed by any two of the above can be mentioned.

[0140] According to the preparation method of the present application, preferably, the conditions of the cyanide reaction include: the reaction temperature is 140-220°C, and preferably 180-190°C; the reaction time is 5-12h, and preferably 7-8h.

[0141] After the reaction is completed, the reaction solution can be refined by a conventional method in the art, and preferably, the reaction solution is subjected to solid-liquid separation, and the obtained is directly used in the next reaction.

[0142] fluorination step

[0143] In the present application, a step of fluorinating a compound having a structure represented by Formula II to obtain a compound having a structure represented by Formula III is also included.

[0144] According to the production method of the present application, preferably, in the fluorination reaction, the fluorinating agent is potassium fluoride and / or sodium fluoride, and more preferably, potassium fluoride.

[0145] According to the production method of the present application, in order to promote the reaction, preferably, the fluorination reaction is performed in the presence of a second catalyst, and the second catalyst is one or more of tetraphenylphosphonium bromide, tetrabutylphosphonium bromide, and tetraethylphosphonium bromide, and more preferably, tetraphenylphosphonium bromide.

[0146] According to the production method of the present application, preferably, in the fluorination reaction, the molar ratio of the compound having a structure represented by Formula II to the second catalyst is 1 : 0.01 to 0.1, and more preferably, 1 : 0.03 to 0.05.

[0147] As a specific example of the molar ratio of the compound having a structure represented by Formula II to the second catalyst, for example, 1 : 0.01, 1 : 0.02, 1 : 0.03, 1 : 0.04, 1 : 0.05, 1 : 0.06, 1 : 0.07, 1 : 0.08, 1 : 0.09, 1 : 0.1, and the like, and a range constituted by any two of the above can be given.

[0148] According to the production method of the present application, preferably, in the fluorination reaction, the molar ratio of the compound having a structure represented by Formula II to the fluorinating agent is 1 : 1 to 2, and more preferably, 1 : 1.1 to 1.3.

[0149] As a specific example of the molar ratio of the compound having a structure represented by Formula II to the fluorinating agent, for example, 1 : 1.1, 1 : 1.2, 1 : 1.3, 1 : 1.4, 1 : 1.5, 1 : 1.6, 1 : 1.7, 1 : 1.8, 1 : 1.9, 1 : 2, and the like, and a range constituted by any two of the above can be given.

[0150] According to the production method of the present application, in order to promote the reaction, preferably, the fluorination reaction is performed in the presence of a fourth solvent, and as the fourth solvent, only a solvent which is inert to the reaction raw materials and which can dissolve the reaction raw materials is necessary, and preferably, the fourth solvent is one or more of N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, and diphenyl ether, and more preferably, dimethyl sulfoxide.

[0151] According to the preparation method of the present application, preferably, the conditions of the fluorination reaction include: the reaction temperature is 120-200°C, preferably 130-140°C; the reaction time is 5-12h, preferably 7-8h.

[0152] After the reaction is completed, the product can be refined by using the conventional method in the art, preferably, the product can be refined by distillation (preferably, rectification) after removing the salt.

[0153] According to the preparation method of the present application, the expensive 2-chloro-4-fluorobenzoic acid is not used, and the cost of raw materials is greatly reduced.

[0154] According to the preparation method of the present application, in the synthetic route of the present application, the selectivity of the nitration reaction is as high as 97% or more, compared with the selectivity of about 80% of the nitration reaction of 2-chloro-4-fluorobenzoic acid, and the generation of by-products can be effectively reduced.

[0155] According to the preparation method of the present application, in the cyanation step, the post-treatment only needs to be solid-liquid separation for the fluorination step; in the fluorination step, the post-treatment only needs to be distillation after removing the salt; in the nitration reaction step, no post-treatment is needed for the hydrolysis reaction step; in the hydrolysis reaction step, the post-treatment only needs to contact the reaction liquid with water to precipitate the compound of formula V to obtain the solid product; in the hydrogenation reaction step, the post-treatment only needs to be solid-liquid separation of the reaction liquid, then the liquid phase is recovered with solvent, and then washed with water to obtain the compound of formula VI; in the esterification reaction step, the post-treatment only needs to recover the solvent of the reaction liquid, and then wash with water to obtain the compound of formula VII; in the sulfonylation reaction step, the post-treatment only needs to recover the solvent of the reaction liquid, and then wash with water to obtain the compound of formula VIII.

[0156] As known from the above description, the post-treatment of each step of the synthesis steps of the present application is very simple, the waste is little, and the yield is high, which is very suitable for industrial production.

[0157] The present application will be described in detail by the following examples, but the present application is not limited to the following examples.

[0158] In the following examples, the raw materials are not particularly specified, and can be obtained by purchase.

[0159] Example 1

[0160]

[0161] 1) Cyanation reaction

[0162] In a 500 mL reaction kettle, compound I 60 g, cuprous cyanide 36 g and dimethyl sulfoxide 160 g were added, stirred at room temperature for 10 minutes, then heated to 190 °C, i.e. dimethyl sulfoxide reflux. After 7 h of stirring at constant temperature, sample control was performed, and the content of compound I was less than 1%. The reaction solution was filtered to remove the cuprous chloride generated in the reaction, to obtain a dimethyl sulfoxide solution of compound II.

[0163] 2) Fluorination reaction

[0164] In a 500 mL reaction kettle, the dimethyl sulfoxide solution of compound II obtained, potassium fluoride 22 g and tetraphenylphosphonium bromide 6.6 g were added, stirred at room temperature for 10 minutes, then heated to 140 °C. After 7 h of reaction at constant temperature, sample control was performed, and the content of compound II was less than 1%. The reaction solution was filtered to remove the potassium nitrite generated, and the filtrate was distilled at a negative pressure of more than -0.095 MPa to obtain compound III (confirmed by comparison with a commercial standard sample), with a content of 98.7% by weight, and a two-step yield of 82%.

[0165] 3) Nitration reaction

[0166] In a 500 mL reaction kettle, compound III 80 g and 98% by weight concentrated sulfuric acid 160 g were added, stirred at room temperature for 10 minutes until completely dissolved. Then 98% by weight fuming nitric acid 34 g was added dropwise, and the temperature was controlled at 30-40 °C; after the addition was completed, stirring was continued for 30 minutes, sample control was performed, and the content of compound III was less than 0.5%. The obtained sulfuric acid solution of compound IV did not require any post-treatment.

[0167] 4) Hydrolysis reaction

[0168] The sulfuric acid solution of compound IV obtained in the above nitration reaction was heated to 110 °C, and reacted for 1 h at constant temperature. Sample control was performed, and the content of compound IV was less than 0.5%. The reaction solution was slowly poured into 200 g of crushed ice under stirring, and the precipitated solid was filtered, and the filter cake was washed with 50 g of ice water twice to obtain white solid compound V (the structure was confirmed by mass spectrometry, HRMS (ESI) calculated value C7H5ClFN2O3 + [M+H] + 218.9967, test value 218.9964.), with a content of 98.4% by weight, and a two-step yield of 96.3%.

[0169] 5) Hydrogenation reaction

[0170] Check the 2L high-pressure reaction kettle equipped with stirring, thermocouple and hydrogenation device, after confirming that everything is normal, compound V 200g, methanol 1.2L and Raney nickel (10g) are added into the high-pressure reaction kettle, nitrogen is replaced for three times, and hydrogen is filled into the system for the last time, then the reaction is stirred at 1.3MPa and 55-60℃ until the kettle pressure no longer decreases. Cool down, open the kettle, and pump out the material, filter and recover the catalyst for use in the next batch, add 0.5L of water after all the methanol in the filtrate is evaporated, cool down to 0-5℃ in ice bath, and keep the temperature for 1h before pumping and filtering, and the filter cake is dried to obtain compound VI (the structure is confirmed by mass spectrometry, HRMS (ESI) calculated value C7H7ClFN2O + [M+H] + 189.0025, test value 189.0020. ), content 97.5wt%, yield 97.7%.

[0171] 6) Esterification reaction

[0172] Compound VI 60g, 1,2-dichloroethane 300g and 100g water are added into a 1L reaction kettle, stirred at room temperature for 10min, and then heated to 70℃. Then 14g of methyl chloroformate is added dropwise; after the addition is completed, the temperature is increased to 1,2-dichloroethane reflux reaction, and after 4h, the sample is taken for control, and the content of compound VI is less than 0.5%. After passing, all the 1,2-dichloroethane is evaporated, 50g of water is added, and the slurry is stirred for 1h, then pumped and filtered, and the filter cake is dried to obtain compound VII (the structure is confirmed by mass spectrometry, HRMS (ESI) calculated value C9H9ClFN2O3 + [M+H] + 247.0280, test value 247.0288. ), content 96.8wt%, yield 98.1%.

[0173] 7) Sulfurylation reaction

[0174] Compound VII 70g, toluene 350g and 88g triethylamine are added into a 1L reaction kettle, stirred at room temperature for 10min, and then heated to 60℃. Then 80g of N-methyl isopropyl sulfonyl chloride is added dropwise; after the addition is completed, the temperature is increased to toluene reflux reaction, and after 4h, the sample is taken for control, and the content of compound VII is less than 0.5%. After passing, all the toluene is evaporated, 150g of water is added, and the slurry is stirred for 1h, then pumped and filtered, and the filter cake is dried to obtain compound VIII (the structure is confirmed by mass spectrometry, HRMS (ESI) calculated value C 13 H 18 ClFN3O5S + [M+H] + 382.0634, test value 382.0639. ), content 98.1wt%, yield 91.1%.

[0175] Example 2

[0176] Example 2 differs from Example 1 in that the cyanating agent used in the cyanating reaction is sodium cyanide in the same molar amount, and the others are the same as Example 1, to obtain compound III, content 95.5 wt%, two-step yield 61.4%.

[0177] Example 3

[0178] Example 3 differs from Example 1 in that the fluorinating agent used in the fluorinating reaction is sodium fluoride in the same molar amount, and the others are the same as Example 1, to obtain compound III, content 95.9 wt%, yield 69.5%.

[0179] Example 4

[0180] Example 4 differs from Example 1 in that the sulfuric acid used in the nitration reaction is 90 wt% sulfuric acid, and the others are the same as Example 1, to obtain compound V, content 97.1 wt%, two-step yield 95.1%.

[0181] Example 5

[0182] Example 5 differs from Example 1 in that 1 equivalent of water is added in the hydrolysis reaction, and the others are the same as Example 1, to obtain compound V, content 75.4 wt%, two-step yield 67.3%.

[0183] Example 6

[0184] Example 6 differs from Example 1 in that the catalyst used in the hydrogenation reaction is palladium-carbon in the same molar amount, and the others are the same as Example 1, to obtain compound VI, content 84.3 wt%, yield 77.5%.

[0185] Example 7

[0186] Example 7 differs from Example 1 in that the solvent used in the hydrogenation reaction is ethanol in the same weight, and the others are the same as Example 1, to obtain compound VI, content 96.9 wt%, yield 95.6%.

[0187] Example 8

[0188] Example 8 differs from Example 1 in that the solvent used in the esterification reaction is dichloromethane in the same weight, and the others are the same as Example 1, to obtain compound VI, content 95.1 wt%, yield 87.9%.

[0189] Example 9

[0190] Example 9 differs from Example 1 in that the same weight of xylene is used in the sulfonylation reaction, and otherwise is identical to Example 1, to give compound VI in 96.9 wt% content and 88.3% yield.

[0191] The above describes the preferred embodiments of the present application in detail, but the present application is not limited thereto. Within the technical concept of the present application, various simple modifications can be made to the technical solutions of the present application, including that each technical feature is combined in any other suitable manner. These simple modifications and combinations should also be considered as disclosed by the present application and fall within the protection scope of the present application.

Claims

1. A method for preparing a bensulfuron-methyl intermediate, characterized in that, This method Includes the following steps, 1) The step of reacting a compound with the structure shown in Formula III with sulfuric acid and nitric acid to nitrate a compound containing the structure shown in Formula IV. 2) The step of hydrolyzing the nitration product obtained in step 1) to obtain the compound with the structure shown in formula V; 3) The step of hydrogenating the compound with the structure shown in Formula V to obtain the compound with the structure shown in Formula VI. 4) The step of esterifying the compound with the structure shown in Formula VI with a chloroformate to obtain the compound with the structure shown in Formula VII; 5) The step of sulfonating the compound with the structure shown in Formula VII with N-methylisopropylamine sulfonyl chloride to obtain the compound with the structure shown in Formula VIII. In formulas VII and VIII, R is an alkyl group having 1-6 carbon atoms.

2. The method according to claim 1, wherein, The concentration of the sulfuric acid is 80% by weight or more, preferably 80-98% by weight; Preferably, the molar ratio of the compound with the structure shown in Formula III to the sulfuric acid is 1:1-15, more preferably 1:2-4; Preferably, the concentration of the nitric acid is 65% by weight or more, and more preferably 65-98% by weight; Preferably, the molar ratio of the compound with the structure shown in Formula III to the nitric acid is 1:1.01-1.1, more preferably 1:1.03-1.05; Preferably, the conditions for the nitration reaction include: a reaction temperature of 10-100℃, preferably 30-40℃; and a reaction time of 0.5-10h, preferably 0.5-2h.

3. The method according to claim 1, wherein, In the hydrolysis reaction, the molar ratio of the compound with the structure shown in Formula IV to the additional water is 1:0-10, preferably without the addition of additional water; Preferably, the conditions for the hydrolysis reaction include: a reaction temperature of 90-180℃, more preferably 100-110℃; and a reaction time of 1-10h, more preferably 1-2h.

4. The method according to any one of claims 1-3, wherein, The hydrogenation reaction is carried out in the presence of a first solvent, which is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, propanol, butanol, toluene, and chlorobenzene, preferably methanol; Preferably, the hydrogenation reaction is carried out in the presence of a first catalyst, which is one or more of Raney nickel, palladium on carbon, and platinum on carbon, preferably Raney nickel; Preferably, in the hydrogenation reaction, the molar mass ratio of the compound with the structure shown in Formula V to the catalyst is 1 mol:(10-20 g), more preferably 1 mol:(12-15 g); Preferably, in the hydrogenation reaction, the reaction pressure is 0.5-2 MPa, more preferably 1-1.3 MPa; Preferably, the hydrogenation reaction conditions include: a reaction temperature of 20-70℃, more preferably 55-60℃; and a reaction time of 2-10h, more preferably 5-6h.

5. The method according to any one of claims 1-3, wherein, In the esterification reaction, the chloroformate is one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate, butyl chloroformate, pentyl chloroformate, and hexyl chloroformate, preferably methyl chloroformate; Preferably, the molar ratio of the compound with the structure shown in compound VI to the chloroformate is 1:1-2, more preferably 1:1.2-1.5; Preferably, the esterification reaction is carried out in the presence of a second solvent, which is one or more of dichloromethane, 1,2-dichloroethane, toluene, xylene, trifluorotoluene, and chlorobenzene, preferably 1,2-dichloroethane; Preferably, the esterification reaction conditions include: a reaction temperature of 40-120℃, more preferably 70-80℃; and a reaction time of 1-10h, more preferably 3-4h.

6. The method according to any one of claims 1-3, wherein, In the sulfonation reaction, the molar ratio of the compound with the structure shown in compound VII to N-methylisopropylamine sulfonyl chloride is 1:1-2, preferably 1:1.2-1.4; Preferably, the sulfonation reaction is carried out in the presence of a third solvent, which is one or more of toluene, xylene, trifluorotoluene, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, preferably toluene; Preferably, the sulfonation reaction is carried out in the presence of an acid-binding agent, which is one or more of triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, preferably triethylamine; Preferably, the molar ratio of the compound with the structure shown in compound VII to the acid-binding agent is 1:2-8, more preferably 1:3-4; Preferably, the conditions for the sulfonation reaction include: a reaction temperature of 50-140°C, more preferably 100-110°C; and a reaction time of 3-10 h, more preferably 5-6 h.

7. The method according to any one of claims 1-3, wherein, The method further includes the step of fluorinating the compound with the structure shown in Formula II to obtain the compound with the structure shown in Formula III; Preferably, in the fluorination reaction, the fluorinating agent is potassium fluoride and / or sodium fluoride, with potassium fluoride being more preferred; Preferably, the fluorination reaction is carried out in the presence of a second catalyst, which is one or more of tetraphenylphosphine bromide, tetrabutylphosphine bromide, and tetraethylphosphine bromide, preferably tetraphenylphosphine bromide; Preferably, in the fluorination reaction, the molar ratio of the compound with the structure shown in Formula II to the second catalyst is 1:0.01-0.1, more preferably 1:0.03-0.05; Preferably, in the fluorination reaction, the molar ratio of the compound with the structure shown in Formula II to the fluorinating reagent is 1:1-2, more preferably 1:1.1-1.3; Preferably, the fluorination reaction is carried out in the presence of a fourth solvent, which is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, and diphenyl ether, preferably dimethyl sulfoxide; Preferably, the fluorination reaction conditions include: a reaction temperature of 120-200℃, more preferably 130-140℃; and a reaction time of 1-10h, more preferably 2-3h.

8. The method according to claim 7, wherein, The method further includes the step of cyaniding the compound with the structure shown in Formula I to obtain the compound with the structure shown in Formula II; Preferably, in the cyanidation reaction, the cyaniding agent is one or more of cuprous cyanide, sodium cyanide and potassium cyanide, preferably cuprous cyanide; Preferably, in the cyanidation reaction, the molar ratio of the compound with the structure shown in Formula I to the cyaniding reagent is 1:1-2, more preferably 1:1.3-1.5; Preferably, the cyanidation reaction is carried out in the presence of a fifth solvent, which is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, and diphenyl ether, preferably dimethyl sulfoxide; Preferably, the cyanidation reaction conditions include: a reaction temperature of 140-220℃, more preferably 180-190℃; and a reaction time of 5-12h, more preferably 7-8h.

9. The method according to any one of claims 1-3, wherein, In formulas VII and VIII, R is an alkyl group having 1-3 carbon atoms.

10. The method according to claim 9, wherein, In formulas VII and VIII, R is a methyl group.

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