Preparation method and application of saflufenacil synthesis intermediate

Abstract

The invention relates to the field of saflufenacil preparation, and discloses a preparation method and application of a saflufenacil synthesis intermediate. According to the method, 4-fluoro-3-aminobenzotrifluoride and chloroformate are used as starting raw materials, the saflufenacil synthesis intermediate shown in the formula (V) is prepared through a synthesis route shown in the reaction formula (a), the yield of the product obtained in each step of reaction is high, the utilization rate of the reaction raw materials is increased, the production cost is reduced, and the method is suitable for industrial production. The method has the advantages of safe and easily-controlled process, mild synthesis conditions and high target product purity and yield, and is beneficial to large-scale production of saflufenacil. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of saflufenacil preparation, and in particular to a preparation method and application of a saflufenacil synthetic intermediate. Background Art

[0002] Saffluamide is a commonly used herbicide with a wide range of crop applicability. It can effectively kill broadleaf weeds, especially weeds resistant to glyphosate or triazine herbicides. It can also be rapidly degraded and meets environmental protection requirements. Therefore, it has broad market prospects.

[0003] Currently, the synthesis of saflufenacil suffers from long routes, harsh conditions, low intermediate yields, and the generation of significant amounts of waste, waste, and other wastes, making it unsuitable for large-scale production. There is an urgent need to develop a synthesis process with milder conditions, simpler steps, and higher intermediate yields to improve intermediate yields and reduce production costs. Summary of the Invention

[0004] The present invention aims to overcome the problems of complex process, harsh conditions and low yield of intermediates in the prior art, and provides a method for preparing a synthetic intermediate of saflufenacil. The method uses 4-fluoro-3-aminobenzotrifluoride and chloroformate as starting materials, and prepares the synthetic intermediate of saflufenacil through four steps of mild reaction conditions. The yield of the product obtained in each reaction step is high, the utilization rate of the reaction raw materials is improved, and the production cost is reduced. The method has the advantages of safe and easy controllable process, mild synthesis conditions, high purity and yield of the target product, and is conducive to large-scale production of saflufenacil.

[0005] In order to achieve the above object, the present invention provides a method for preparing a synthetic intermediate of saflufenacil represented by formula (V), comprising the following steps:

[0006] (1) reacting 4-fluoro-3-aminobenzotrifluoride with chloroformate in a polar solvent A to obtain a compound represented by formula (I);

[0007] (2) in the presence of a first metal catalyst, in a polar aprotic solvent B, chlorinating the compound represented by formula (I) with a chlorinating agent to obtain a compound represented by formula (II);

[0008] (3) in the presence of an alkaline substance, in a polar aprotic solvent C, reacting the compound represented by formula (II) with 3-amino-4,4,4-trifluorocrotonate, and then reacting the reaction product with dimethyl sulfate to obtain a compound represented by formula (III);

[0009] (4) hydrolyzing the compound represented by formula (III) with sulfuric acid in the presence of a second metal catalyst;

[0010]

[0011] Wherein, R is a C1-C6 alkyl group, the active component of the first metal catalyst is at least one of nickel, cobalt, aluminum and iron, the second metal catalyst is at least one of copper acetate, copper sulfate, copper nitrate and copper chloride, the polar solvent A is at least one of dichloroethane, toluene, chlorobenzene and xylene, and the polar aprotic solvent B and the polar aprotic solvent C are each at least one of acetonitrile, dichloroethane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

[0012] Preferably, in step (1), the reaction conditions include: temperature of 40-120° C., and time of 8-16 h.

[0013] Preferably, in step (1), the molar ratio of the 4-fluoro-3-aminobenzotrifluoride to the chloroformate is 1:1-1.5.

[0014] Preferably, in step (1), the structure of the chloroformate is as shown in formula (IV):

[0015]

[0016] Wherein, R is a C1-C6 alkyl group.

[0017] Preferably, R is methyl, ethyl, propyl or butyl.

[0018] Preferably, in step (2), the conditions of the chlorination reaction include: temperature of 10-100° C. and time of 1-8 h.

[0019] Preferably, in step (2), the molar ratio of the compound represented by formula (I) to the chlorinating agent is 1:1.1-2, and the molar ratio of the compound represented by formula (I) to the first metal catalyst is 1:0.01-0.2.

[0020] Preferably, in step (2), the chlorinating agent is at least one of sulfonyl chloride, thionyl chloride and chlorine.

[0021] Preferably, in step (2), the polar aprotic solvent B is at least one of acetonitrile, dichloroethane and dichloromethane.

[0022] Preferably, in step (3), the conditions of the first reaction include: temperature of 100-230° C., and time of 5-15 h.

[0023] Preferably, in step (3), the conditions of the second reaction include: temperature of 10-40° C. and time of 1-10 h.

[0024] Preferably, in step (3), the molar ratio of the compound represented by formula (II) to the alkaline substance is 1:2.1-3.5.

[0025] Preferably, in step (3), the alkaline substance is at least one of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

[0026] Preferably, in step (3), the molar ratio of the compound represented by formula (II) to the 3-amino-4,4,4-trifluorocrotonate is 1:1-1.5, and the molar ratio of the compound represented by formula (II) to the dimethyl sulfate is 1:1-2.

[0027] Preferably, in step (3), the polar aprotic solvent C is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

[0028] Preferably, in step (4), the conditions of the hydrolysis reaction include: temperature of 20-150° C. and time of 2-8 h.

[0029] Preferably, in step (4), the molar ratio of the compound represented by formula (III) to the sulfuric acid is 1:1-2, and the molar ratio of the compound represented by formula (III) to the second metal catalyst is 1:0.01-0.1.

[0030] According to the preparation method of the synthetic intermediate of saflufenacil of the present invention, 4-fluoro-3-aminobenzotrifluoride and chloroformate are used as starting materials, and the synthetic intermediate of saflufenacil is prepared through four steps of mild reaction conditions. The yield of the product obtained in each reaction step is high, the utilization rate of the reaction raw materials is improved, and the production cost is reduced. The method has the advantages of safe and easy controllable process, mild synthesis conditions, high purity and yield of the target product, and is conducive to the large-scale production of saflufenacil. DETAILED DESCRIPTION

[0031] The following is a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention.

[0032] The endpoints of the ranges and any values disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0033] The method for preparing the synthetic intermediate of saflufenacil represented by formula (V) of the present invention comprises the following steps:

[0034] (1) reacting 4-fluoro-3-aminobenzotrifluoride with chloroformate in a polar solvent A to obtain a compound represented by formula (I);

[0035] (2) in the presence of a first metal catalyst, in a polar aprotic solvent B, chlorinating the compound represented by formula (I) with a chlorinating agent to obtain a compound represented by formula (II);

[0036] (3) in the presence of an alkaline substance, in a polar aprotic solvent C, reacting the compound represented by formula (II) with 3-amino-4,4,4-trifluorocrotonate, and then reacting the reaction product with dimethyl sulfate to obtain a compound represented by formula (III);

[0037] (4) hydrolyzing the compound represented by formula (III) with sulfuric acid in the presence of a second metal catalyst;

[0038]

[0039] Wherein, R is a C1-C6 alkyl group, the active component of the first metal catalyst is at least one of nickel, cobalt, aluminum and iron, the second metal catalyst is at least one of copper acetate, copper sulfate, copper nitrate and copper chloride, the polar solvent A is at least one of dichloroethane, toluene, chlorobenzene and xylene, and the polar aprotic solvent B and the polar aprotic solvent C are each at least one of acetonitrile, dichloroethane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

[0040] In the present invention, the C1-C6 alkyl group may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, an isohexyl group or a 3,3-dimethylbutyl group.

[0041] In the method of the present invention, preferably, in step (1), the 3-amino-4,4,4-trifluorocrotonate may be any type of 3-amino-4,4,4-trifluorocrotonate that is stable and meets the requirements, more preferably methyl 3-amino-4,4,4-trifluorocrotonate and / or ethyl 3-amino-4,4,4-trifluorocrotonate, and most preferably ethyl 3-amino-4,4,4-trifluorocrotonate.

[0042] In the method of the present invention, preferably, in step (1), the first metal catalyst is at least one of ferric chloride, cobalt chloride, aluminum chloride and nickel chloride. More preferably, the first metal catalyst is at least one of ferric chloride, nickel chloride and aluminum chloride. In a specific embodiment of the present invention, other salts containing the same metal ions as the above-mentioned metal chloride salts can also be used as the first metal catalyst. The present invention preferably uses metal chloride salts to avoid potential interference with the reaction caused by the introduction of other different acid radical ions.

[0043] In the method of the present invention, preferably, in step (1), the reaction conditions include: a temperature of 40-120° C. and a time of 8-16 hours. More preferably, the reaction conditions include: a temperature of 50-110° C. and a time of 9-15 hours. Most preferably, the reaction conditions include: a temperature of 60-90° C. and a time of 10-14 hours. In the present invention, the above reaction conditions can fully react the raw materials and obtain a higher yield of the intermediate.

[0044] In the method of the present invention, preferably, in step (1), the molar ratio of the 4-fluoro-3-aminobenzotrifluoride to the chloroformate is 1:1-1.5, more preferably 1:1.1-1.3. In the present invention, the above-mentioned ratios can fully react the 4-fluoro-3-aminobenzotrifluoride and improve the purity of the intermediate.

[0045] In the method of the present invention, preferably, in step (1), the molar mass ratio of the 4-fluoro-3-aminobenzotrifluoride to the polar solvent A is 1 mol:4000-6000 g, more preferably 1 mol:4500-5500 g. In the present invention, the above amount can fully disperse the raw materials, allowing the reaction to proceed fully, which is conducive to obtaining a higher product yield.

[0046] In the method of the present invention, preferably, in step (1), the structure of the chloroformate is as shown in formula (IV):

[0047]

[0048] wherein R is a C1-C6 alkyl group, more preferably a C1-C5 alkyl group, and most preferably a C1-C4 alkyl group.

[0049] In the method of the present invention, preferably, R is methyl, ethyl, propyl or butyl.

[0050] In the present invention, the above-mentioned types of chloroformates are selected to obtain a relatively stable and high-purity compound represented by formula (I). The shorter R substituent can reduce the occurrence of side reactions and further improve the purity of the intermediate product. In a specific embodiment of the present invention, a single type of chloroformates can be used, or a mixture of multiple chloroformates conforming to the structure represented by formula (IV) can be used. For ease of calculation, it is preferred to use a single type of chloroformates.

[0051] In the method of the present invention, preferably, in step (2), the conditions for the chlorination reaction include: a temperature of 10-100°C and a time of 1-8 hours. More preferably, the conditions for the chlorination reaction include: a temperature of 10-80°C and a time of 2-7 hours. Most preferably, the conditions for the chlorination reaction include: a temperature of 15-40°C and a time of 2-6 hours. In the present invention, the above conditions can ensure sufficient chlorination without generating additional chlorination by-products.

[0052] In the method of the present invention, preferably, in step (2), the molar ratio of the compound represented by formula (I) to the chlorinating agent is 1:1.1-2, more preferably 1:1.1-1.8, and most preferably 1:1.1-1.6.

[0053] In the method of the present invention, preferably, in step (2), the molar ratio of the compound represented by formula (I) to the first metal catalyst is 1:0.01-0.2, more preferably 1:0.01-0.18, and most preferably 1:0.02-0.15.

[0054] In the present invention, the above-mentioned amounts are used to obtain a high-purity intermediate product for the next reaction, thereby improving raw material utilization and reducing raw material waste. In a specific embodiment, the polar solvent A and the first metal catalyst used can be recycled and reused through the separation step to further reduce production costs.

[0055] In the method of the present invention, preferably, in step (2), the chlorinating agent is at least one of sulfonyl chloride, thionyl chloride and chlorine. More preferably, the chlorinating agent is thionyl chloride and / or chlorine.

[0056] In the method of the present invention, preferably, in step (2), the polar aprotic solvent B is at least one of acetonitrile, dichloroethane and dichloromethane. More preferably, the polar aprotic solvent B is acetonitrile and / or dichloroethane.

[0057] In the method of the present invention, preferably, in step (3), the conditions for the first reaction include: a temperature of 100-230°C and a time of 5-15 hours. More preferably, the conditions for the first reaction include: a temperature of 105-200°C and a time of 6-14 hours. Most preferably, the conditions for the first reaction include: a temperature of 110-160°C and a time of 7-13 hours.

[0058] In the method of the present invention, preferably, in step (3), the conditions for the second reaction include: a temperature of 10-40°C and a time of 1-10 hours. More preferably, the conditions for the second reaction include: a temperature of 10-35°C and a time of 2-9 hours. Most preferably, the conditions for the second reaction include: a temperature of 15-30°C and a time of 3-8 hours.

[0059] In the present invention, the above conditions are adopted, so that the compound represented by formula (II) can first fully react with 3-amino-4,4,4-trifluorocrotonate, then reduce the temperature to room temperature, and then react with dimethyl sulfate to obtain the compound represented by formula (III). The two-stage reaction is carried out continuously without the need for product separation, saving a synthesis step. In a specific embodiment of the present invention, sampling detection can also be set in the two-stage continuous reaction, and liquid chromatography analysis is used to monitor whether the compound represented by formula (II) has fully reacted. After determining that the reaction is sufficient, the reaction with dimethyl sulfate is carried out, and the synthesis process is adjusted in time to ensure the high yield and purity of the compound represented by formula (III), which is beneficial to the high yield of the synthetic intermediate of benzylpyrasulfuron.

[0060] In the method of the present invention, preferably, in step (3), the molar ratio of the compound represented by formula (II) to the alkaline substance is 1:2.1-3.5, more preferably 1:2.2-3.3, and most preferably 1:2.3-3.

[0061] In the method of the present invention, preferably, in step (3), the alkaline substance is at least one of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate. More preferably, the alkaline substance is potassium carbonate and / or sodium carbonate.

[0062] In the present invention, the above-mentioned types and amounts of alkaline substances can provide a suitable alkaline environment for the reaction, and carbonates or bicarbonates will not introduce many impurity groups, which is conducive to maintaining the purity of the reaction product.

[0063] In the method of the present invention, preferably, in step (3), the molar ratio of the compound represented by formula (II) to the 3-amino-4,4,4-trifluorocrotonate is 1:1-1.5, more preferably 1:1-1.4, and most preferably 1:1.1-1.2.

[0064] In the method of the present invention, preferably, in step (3), the molar ratio of the compound represented by formula (II) to the dimethyl sulfate is 1:1-2, more preferably 1:1-1.8, and most preferably 1:1.1-1.7.

[0065] In the present invention, the use of the above-mentioned 3-amino-4,4,4-trifluorocrotonate and dimethyl sulfate in an amount slightly greater than that of the compound represented by formula (II) is beneficial to the full reaction of the compound represented by formula (II) and maintains the purity and yield of the compound represented by formula (III) obtained by the reaction.

[0066] In the method of the present invention, preferably, in step (3), the polar aprotic solvent C is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone. More preferably, the polar aprotic solvent C is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0067] In the method of the present invention, preferably, in step (4), the conditions for the hydrolysis reaction include: a temperature of 20-150°C and a time of 2-8 hours. More preferably, the conditions for the hydrolysis reaction include: a temperature of 40-140°C and a time of 3-7 hours. Most preferably, the conditions for the hydrolysis reaction include: a temperature of 50-120°C and a time of 4-6 hours. In the present invention, the above conditions can be used to fully hydrolyze the compound represented by formula (III) into the synthetic intermediate of benzylpyrasulfuron represented by formula (V), thereby maintaining the purity of the product and a high yield.

[0068] In the method of the present invention, preferably, in step (4), the molar ratio of the compound represented by formula (III) to the sulfuric acid is 1:1-2, more preferably 1:1-1.8, and most preferably 1:1-1.5.

[0069] In the method of the present invention, preferably, in step (4), the molar ratio of the compound represented by formula (III) to the second metal catalyst is 1:0.01-0.1, more preferably 1:0.02-0.09, and most preferably 1:0.02-0.08.

[0070] In a specific embodiment of the present invention, after any reaction in steps (1) to (4) is completed, the mixture after the reaction can be sampled and analyzed by high performance liquid chromatography to detect whether the reaction is complete, so as to further monitor and improve the reaction yield and the purity of the target product of each step. The criterion for judging whether the reaction is complete is: when the percentage of the raw material peak area to the total peak area is less than 0.2%, the reaction of the step is considered to be complete, wherein the raw material peak refers to the starting reaction material used in steps (1) to (4), which is 4-fluoro-3-aminotrifluorotoluene in step (1), the compound represented by formula (I) in step (2), the compound represented by formula (II) in step (3), and the compound represented by formula (III) in step (4).

[0071] In a specific embodiment of the present invention, after any reaction in steps (1) to (4) is completed, a separation step may be further included to purify the product obtained by the reaction to provide a high-purity reaction substrate for the subsequent synthesis step, while removing other reaction raw materials and solvents used in the reaction to ensure the purity of each step of the reaction, improve the purity of the final product, and recover some of the usable raw materials and solvents, thereby further reducing costs. The separation step can adopt various separation methods commonly used in the art. In the present invention, the solvent can be removed by direct vacuuming or reduced pressure distillation.

[0072] In a specific embodiment, as shown in reaction formula (a), the specific process of the preparation method of the synthetic intermediate of saflufenacil of the present invention may include:

[0073]

[0074] (1) reacting 4-fluoro-3-aminobenzotrifluoride with chloroformate in a polar solvent A at 40-120° C. for 8-16 hours to obtain a compound represented by formula (I), wherein the polar solvent A is at least one of dichloroethane, toluene, chlorobenzene, and xylene, the molar ratio of the 4-fluoro-3-aminobenzotrifluoride to the chloroformate is 1:1-1.5, and the molar mass ratio of the 4-fluoro-3-aminobenzotrifluoride to the polar solvent A is 1 mol:4000-6000 g;

[0075] (2) in the presence of a first metal catalyst, in a polar aprotic solvent B, reacting a compound represented by formula (I) with a chlorinating agent at 10-100° C. for 1-8 hours to obtain a compound represented by formula (II), wherein the molar ratio of the compound represented by formula (I) to the first metal catalyst is 1:0.01-0.2, the active component of the first metal catalyst is at least one of nickel, cobalt, aluminum and iron, the molar ratio of the compound represented by formula (I) to the chlorinating agent is 1:1.1-2, the chlorinating agent is at least one of sulfonyl chloride, thionyl chloride and chlorine, and the polar aprotic solvent B is at least one of acetonitrile, dichloroethane and dichloromethane;

[0076] (3) In the presence of an alkaline substance, in a polar aprotic solvent C, reacting the compound represented by formula (II) with 3-amino-4,4,4-trifluorocrotonate at 100-230° C. for 5-15 h, and then reacting the reaction product with dimethyl sulfate at 10-40° C. for 1-10 h to obtain the compound represented by formula (III), wherein the molar ratio of the compound represented by formula (II) to the 3-amino-4,4,4-trifluorocrotonate is 1:1. : 1-1.5, the molar ratio of the compound represented by formula (II) to the dimethyl sulfate is 1: 1-2, the molar ratio of the compound represented by formula (II) to the alkaline substance is 1: 2.1-3.5, the alkaline substance is at least one of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and the polar aprotic solvent C is at least one of N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone;

[0077] (4) hydrolyzing the compound represented by formula (III) with sulfuric acid at 20-100° C. for 2-8 h in the presence of a second metal catalyst, wherein the molar ratio of the compound represented by formula (III) to the sulfuric acid is 1:1-2, and the molar ratio of the compound represented by formula (III) to the second metal catalyst is 1:0.01-0.1, and the second metal catalyst is at least one of copper acetate, copper sulfate, copper nitrate, and copper chloride;

[0078]

[0079] Wherein, R is a C1-C6 alkyl group.

[0080] The following examples further illustrate the preparation method and application of the saflufenacil synthetic intermediate of the present invention. The examples are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operating processes, but the scope of protection of the present invention is not limited to the following examples.

[0081] The experimental methods in the following examples, unless otherwise specified, are all conventional methods in the art. The experimental materials used in the following examples, unless otherwise specified, are all commercially available.

[0082] Example 1

[0083] (1) Add 0.1 mol of 4-fluoro-3-aminobenzotrifluoride and 500 g of dichloromethane to a 1 L four-necked flask, stir evenly, and then heat to 75° C. Then, add 0.11 mol of methyl chloroformate dropwise while stirring. After the addition is complete, continue stirring for 11 hours, then cool to room temperature, and remove the solvent under reduced pressure to obtain the compound represented by formula (I);

[0084] (2) Add 0.1 mol of the compound represented by formula (I), 0.01 mol of nickel chloride, and 100 g of acetonitrile to a 1 L four-necked flask, introduce 0.15 mol of chlorine gas at 25° C., continue stirring for 3 h, then cool to room temperature, remove the solvent under reduced pressure, and then concentrate and crystallize to obtain the compound represented by formula (II);

[0085] (3) 0.1 mol of the compound represented by formula (II), 100 g of N,N-dimethylformamide, and 0.3 mol of potassium carbonate were added to a four-necked flask with a volume of 1 L, and then heated to 130° C. 0.12 mol of 3-amino-4,4,4-trifluorocrotonate was added dropwise while refluxing. After the addition was complete, reflux was continued for 10 hours. After cooling to room temperature, 0.15 mol of dimethyl sulfate was added dropwise. After the addition was complete, the reaction was continued for 5 hours. After filtration and removal of the solvent under reduced pressure, the compound represented by formula (III) was obtained.

[0086] (4) To a 1 L four-necked flask, 0.1 mol of the compound represented by formula (III), 10 g of sulfuric acid, 100 g of n-butanol, and 1 g of copper acetate were added. The mixture was then heated to 120° C. and refluxed for 5 h. The temperature was then lowered to room temperature. The solvent was removed under reduced pressure to obtain the synthetic intermediate A1 of saflufenacil.

[0087] Example 2

[0088] (1) Add 0.1 mol of 4-fluoro-3-aminobenzotrifluoride and 550 g of dichloromethane to a 1 L four-necked flask, stir evenly, and then heat to 80° C. Then, add 0.10 mol of methyl chloroformate dropwise while stirring. After the addition is complete, continue stirring for 10 hours, then cool to room temperature, and remove the solvent under reduced pressure to obtain the compound represented by formula (I);

[0089] (2) To a 1 L four-necked flask, add 0.1 mol of the compound represented by formula (I), 0.005 mol of ferric chloride, and 100 g of acetonitrile, introduce 0.15 mol of chlorine gas at 35° C., continue stirring for 3 h, then cool to room temperature, remove the solvent under reduced pressure, and then concentrate and crystallize to obtain the compound represented by formula (II);

[0090] (3) 0.1 mol of the compound represented by formula (II), 100 g of N,N-dimethylformamide, and 0.32 mol of potassium carbonate were added to a four-necked flask with a volume of 1 L, and then heated to 120° C. 0.11 mol of 3-amino-4,4,4-trifluorocrotonate was added dropwise while refluxing. After the addition was complete, reflux was continued for 9 hours. After cooling to room temperature, 0.13 mol of dimethyl sulfate was added dropwise. After the addition was complete, the reaction was continued for 4 hours. After filtration and removal of the solvent under reduced pressure, the compound represented by formula (III) was obtained.

[0091] (4) To a 1 L four-necked flask, 0.1 mol of the compound represented by formula (III), 12 g of sulfuric acid, 100 g of n-butanol, and 1 g of copper acetate were added. The mixture was then heated to 110° C. and refluxed for 6 h. The temperature was then lowered to room temperature. The solvent was removed under reduced pressure to obtain the synthetic intermediate A2 of saflufenacil.

[0092] Example 3

[0093] (1) To a 1 L four-necked flask, add 0.1 mol of 4-fluoro-3-aminobenzotrifluoride and 450 g of dichloromethane, stir evenly, and then heat to 60° C., then dropwise add 0.14 mol of methyl chloroformate while stirring. After the addition is complete, continue stirring for 13 h, then cool to room temperature, and remove the solvent under reduced pressure to obtain the compound represented by formula (I);

[0094] (2) To a 1 L four-necked flask, add 0.1 mol of the compound represented by formula (I), 0.005 mol of ferric chloride, and 100 g of acetonitrile, introduce 0.2 mol of chlorine gas at 20° C., continue stirring for 3 h, then cool to room temperature, remove the solvent under reduced pressure, and then concentrate and crystallize to obtain the compound represented by formula (II);

[0095] (3) 0.1 mol of the compound represented by formula (II), 100 g of N,N-dimethylformamide, and 0.29 mol of potassium carbonate were added to a four-necked flask with a volume of 1 L, and then heated to 140° C. 0.13 mol of 3-amino-4,4,4-trifluorocrotonate was added dropwise while refluxing. After the addition was complete, reflux was continued for 12 hours. After cooling to room temperature, 0.18 mol of dimethyl sulfate was added dropwise. After the addition was complete, the reaction was continued for 6 hours. After filtration and removal of the solvent under reduced pressure, the compound represented by formula (III) was obtained.

[0096] (4) To a 1 L four-necked flask, 0.1 mol of the compound represented by formula (III), 11 g of sulfuric acid, 100 g of n-butanol, and 1 g of copper acetate were added. The mixture was then heated to 90° C. and refluxed for 4 h. The temperature was then lowered to room temperature. The solvent was removed under reduced pressure to obtain the synthetic intermediate A3 of saflufenacil.

[0097] Example 4

[0098] (1) Add 0.1 mol of 4-fluoro-3-aminobenzotrifluoride and 500 g of chlorobenzene to a 1 L four-necked flask, stir evenly, and then heat to 85° C. Then, add 0.11 mol of ethyl chloroformate dropwise while stirring. After the addition is complete, continue stirring for 12 h, then cool to room temperature, and remove the solvent under reduced pressure to obtain the compound represented by formula (I);

[0099] (2) To a 1 L four-necked flask, add 0.1 mol of the compound represented by formula (I), 0.01 mol of aluminum chloride, and 100 g of dichloromethane. Add 0.12 mol of sulfuryl chloride at 30° C., continue stirring for 4 h, then cool to room temperature, remove the solvent under reduced pressure, and then concentrate and crystallize to obtain the compound represented by formula (II);

[0100] (3) 0.1 mol of the compound represented by formula (II), 100 g of N,N-dimethylacetamide, and 0.3 mol of sodium carbonate were added to a four-necked flask with a volume of 1 L, and then heated to 130° C. 0.12 mol of 3-amino-4,4,4-trifluorocrotonate was added dropwise while refluxing. After the addition was complete, reflux was continued for 10 hours. After cooling to room temperature, 0.15 mol of dimethyl sulfate was added dropwise. After the addition was complete, the reaction was continued for 5 hours. After filtration and removal of the solvent under reduced pressure, the compound represented by formula (III) was obtained.

[0101] (4) To a 1 L four-necked flask, 0.1 mol of the compound represented by formula (III), 10 g of sulfuric acid, 100 g of n-butanol, and 1 g of copper sulfate were added. The mixture was then heated to 120° C. and refluxed for 5 h. The temperature was then lowered to room temperature. The solvent was removed under reduced pressure to obtain the synthetic intermediate A4 of saflufenacil.

[0102] Example 5

[0103] (1) Add 0.1 mol of 4-fluoro-3-aminobenzotrifluoride and 500 g of toluene to a 1 L four-necked flask, stir evenly, and then heat to 80° C. Then, add 0.11 mol of propyl chloroformate dropwise while stirring. After the addition is complete, continue stirring for 11 hours, then cool to room temperature, and remove the solvent under reduced pressure to obtain the compound represented by formula (I);

[0104] (2) To a 1 L four-necked flask, add 0.1 mol of the compound represented by formula (I), 0.01 mol of ferric chloride, and 100 g of dichloroethane. Add 0.12 mol of thionyl chloride at 25° C., continue stirring for 4 h, then cool to room temperature, remove the solvent under reduced pressure, and then concentrate and crystallize to obtain the compound represented by formula (II);

[0105] (3) 0.1 mol of the compound represented by formula (II), 100 g of dimethyl sulfoxide, and 0.34 mol of sodium bicarbonate were added to a 1 L four-necked flask, and then heated to 130° C. 0.12 mol of 3-amino-4,4,4-trifluorocrotonate was added dropwise while refluxing. After the addition was complete, reflux was continued for 10 h. After cooling to room temperature, 0.15 mol of dimethyl sulfate was added dropwise. After the addition was complete, the reaction was continued for 5 h. After filtration and removal of the solvent under reduced pressure, the compound represented by formula (III) was obtained.

[0106] (4) To a 1 L four-necked flask, 0.1 mol of the compound represented by formula (III), 10 g of sulfuric acid, 100 g of n-butanol, and 1 g of copper nitrate were added. The mixture was then heated to 120° C. and refluxed for 5 h. The temperature was then lowered to room temperature. The solvent was removed under reduced pressure to obtain the synthetic intermediate A5 of saflufenacil.

[0107] Example 6

[0108] (1) Add 0.1 mol of 4-fluoro-3-aminobenzotrifluoride and 500 g of xylene to a 1 L four-necked flask, stir evenly, and then heat to 90° C. Then, add 0.11 mol of butyl chloroformate dropwise while stirring. After the addition is complete, continue stirring for 9 h, then cool to room temperature, and remove the solvent under reduced pressure to obtain the compound represented by formula (I);

[0109] (2) Add 0.1 mol of the compound represented by formula (I), 0.01 mol of nickel chloride, and 100 g of acetonitrile to a 1 L four-necked flask, introduce 0.12 mol of chlorine gas at 60° C., continue stirring for 2 h, then cool to room temperature, remove the solvent under reduced pressure, and then concentrate and crystallize to obtain the compound represented by formula (II);

[0110] (3) 0.1 mol of the compound represented by formula (II), 100 g of N,N-dimethylformamide, and 0.3 mol of sodium carbonate were added to a four-necked flask with a volume of 1 L, and then heated to 150° C. 0.11 mol of 3-amino-4,4,4-trifluorocrotonate was added dropwise while refluxing. After the addition was complete, reflux was continued for 8 h. After cooling to room temperature, 0.13 mol of dimethyl sulfate was added dropwise. After the addition was complete, the reaction was continued for 4 h. After filtration and removal of the solvent under reduced pressure, the compound represented by formula (III) was obtained.

[0111] (4) To a 1 L four-necked flask, 0.1 mol of the compound represented by formula (III), 10 g of sulfuric acid, 100 g of n-butanol, and 1 g of copper acetate were added. The mixture was then heated to 90° C. and refluxed for 5 h. The temperature was then lowered to room temperature. The solvent was removed under reduced pressure to obtain the synthetic intermediate A6 of saflufenacil.

[0112] Example 7

[0113] (1) Add 0.1 mol of 4-fluoro-3-aminobenzotrifluoride and 500 g of dichloromethane to a 1 L four-necked flask, stir evenly, and then heat to 50° C. Then, add 0.15 mol of methyl chloroformate dropwise while stirring. After the addition is complete, continue stirring for 16 hours, then cool to room temperature, and remove the solvent under reduced pressure to obtain the compound represented by formula (I);

[0114] (2) To a 1 L four-necked flask, add 0.1 mol of the compound represented by formula (I), 0.01 mol of nickel chloride, and 100 g of acetonitrile, introduce 0.15 mol of chlorine gas at 15° C., continue stirring for 6 h, then cool to room temperature, remove the solvent under reduced pressure, and then concentrate and crystallize to obtain the compound represented by formula (II);

[0115] (3) 0.1 mol of the compound represented by formula (II), 100 g of N,N-dimethylformamide, and 0.3 mol of potassium carbonate were added to a four-necked flask with a volume of 1 L, and then heated to 110° C. 0.14 mol of 3-amino-4,4,4-trifluorocrotonate was added dropwise while refluxing. After the addition was complete, reflux was continued for 14 hours. After cooling to room temperature, 0.19 mol of dimethyl sulfate was added dropwise. After the addition was complete, the reaction was continued for 7 hours. After filtration and removal of the solvent under reduced pressure, the compound represented by formula (III) was obtained.

[0116] (4) To a 1 L four-necked flask, 0.1 mol of the compound represented by formula (III), 10 g of sulfuric acid, 100 g of n-butanol, and 1 g of copper acetate were added. The mixture was then heated to 80° C. and refluxed for 5 h. The temperature was then lowered to room temperature. The solvent was removed under reduced pressure to obtain the synthetic intermediate A7 of saflufenacil.

[0117] Comparative Example 1

[0118] The method of Example 1 was adopted, except that nickel chloride was not added in step (2) (ie, no catalyst was used), to obtain the synthetic intermediate D1 of saflufenacil.

[0119] Comparative Example 2

[0120] The method of Example 1 is adopted, except that potassium carbonate is not added in step (3) (ie, no alkaline substance is added), and the obtained synthetic intermediate D2 of saflufenacil is obtained.

[0121] Test Case

[0122] The purity of the saflufenacil synthetic intermediates A1-A7 and D1-D2 prepared in Examples 1-7 and Comparative Example 1-2, as well as the purity of the compounds of formula (I) to (III) obtained after the reaction of steps (1) to (3) in Examples 1-7 and Comparative Example 1-2, were tested using an Agilent 1260 high performance liquid chromatography analyzer. The results are shown in Table 1:

[0123] Table 1

[0124]

[0125]

[0126] Based on the above purity test results, the yield of the compound represented by formula (II) was calculated based on 4-fluoro-3-aminobenzotrifluoride, the yield of the compound represented by formula (II) was calculated based on the compound represented by formula (I), the yield of the compound represented by formula (III) was calculated based on the compound represented by formula (II), and the yield of the synthetic intermediate of saflufenacil was calculated based on the compound represented by formula (III). The results are shown in Table 2:

[0127] Table 2

[0128]

[0129] It can be seen that according to the preparation method of the synthetic intermediate of saflufenacil described in the present invention, 4-fluoro-3-aminobenzotrifluoride and chloroformate are used as starting materials. After four-step reaction, the synthetic intermediate of saflufenacil can be prepared with high yield and purity, and the product of each step of the reaction generally has a yield close to 90% and a purity generally above 94%, indicating that the utilization rate of the reaction raw materials is high, the side reactions are few, and the waste generated is less, which effectively improves the production efficiency and reduces the production cost; the solvent used in each step of the reaction can be recycled and reused through the separation step, which can further reduce the cost; and the reaction conditions in each step are mild, the process is safe and easy to control, which is conducive to the large-scale production of saflufenacil.

[0130] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with this technical field can easily think of changes or replacements within the technical scope disclosed by the present invention, which should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing a synthetic intermediate of saflufenacil represented by formula (V), characterized in that: The method comprises the following steps: (1) reacting 4-fluoro-3-aminobenzotrifluoride with chloroformate in a polar solvent A to obtain a compound represented by formula (I); (2) in the presence of a first metal catalyst, in a polar aprotic solvent B, chlorinating the compound represented by formula (I) with a chlorinating agent to obtain a compound represented by formula (II); (3) in the presence of an alkaline substance, in a polar aprotic solvent C, reacting the compound represented by formula (II) with 3-amino-4,4,4-trifluorocrotonate, and then reacting the reaction product with dimethyl sulfate to obtain a compound represented by formula (III); (4) hydrolyzing the compound represented by formula (III) with sulfuric acid in the presence of a second metal catalyst; Wherein, R is a C1-C6 alkyl group, the active component of the first metal catalyst is at least one of nickel, cobalt, aluminum and iron, the second metal catalyst is at least one of copper acetate, copper sulfate, copper nitrate and copper chloride, the polar solvent A is at least one of dichloroethane, toluene, chlorobenzene and xylene, and the polar aprotic solvent B and the polar aprotic solvent C are each at least one of acetonitrile, dichloroethane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

2. The method according to claim 1, characterized in that In step (1), the reaction conditions include: temperature of 40-120° C. and time of 8-16 h.

3. The method according to claim 1 or 2, characterized in that In step (1), the molar ratio of the 4-fluoro-3-aminobenzotrifluoride to the chloroformate is 1:1-1.

5.

4. The method according to any one of claims 1 to 3, characterized in that In step (1), the structure of the chloroformate is shown in formula (IV): Wherein, R is a C1-C6 alkyl group; Preferably, R is methyl, ethyl, propyl or butyl.

5. The method according to claim 1, wherein In step (2), the conditions of the chlorination reaction include: temperature of 10-100° C. and time of 1-8 h.

6. The method according to claim 1 or 5, characterized in that In step (2), the molar ratio of the compound represented by formula (I) to the chlorinating agent is 1:1.1-2, and the molar ratio of the compound represented by formula (I) to the first metal catalyst is 1:0.01-0.

2.

7. The method according to any one of claims 1 or 5-6, characterized in that In step (2), the chlorinating agent is at least one of sulfuryl chloride, thionyl chloride and chlorine.

8. The method according to any one of claims 1 or 5-7, characterized in that In step (2), the polar aprotic solvent B is at least one of acetonitrile, dichloroethane and dichloromethane.

9. The method according to claim 1, characterized in that In step (3), the conditions of the first reaction include: temperature of 100-230° C., and time of 5-15 h.

10. The method according to claim 1 or 9, characterized in that In step (3), the conditions of the second reaction include: temperature of 10-40° C. and time of 1-10 h.

11. The method according to any one of claims 1 or 9-10, characterized in that: In step (3), the molar ratio of the compound represented by formula (II) to the alkaline substance is 1:2.1-3.5; Preferably, the alkaline substance is at least one of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

12. The method according to any one of claims 1 or 9 to 11, characterized in that: In step (3), the molar ratio of the compound represented by formula (II) to the 3-amino-4,4,4-trifluorocrotonate is 1:1-1.5, and the molar ratio of the compound represented by formula (II) to the dimethyl sulfate is 1:1-2.

13. The method according to any one of claims 1 or 9 to 12, characterized in that: In step (3), the polar aprotic solvent C is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone.

14. The method according to claim 1, wherein In step (4), the conditions of the hydrolysis reaction include: temperature of 20-150° C. and time of 2-8 h.

15. The method according to claim 1, wherein In step (4), the molar ratio of the compound represented by formula (III) to the sulfuric acid is 1:1-2, and the molar ratio of the compound represented by formula (III) to the second metal catalyst is 1:0.01-0.1.

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