Preparation method of saflufenacil

Abstract

The invention discloses a preparation method of saflufenacil, and belongs to the field of herbicide preparation, the preparation method comprises the following steps: (1) mixing 2-chloro-4-fluoro-5-(3-methyl-2, 6-dioxo-4-(trifluoromethyl)-2, 3-dihydropyrimidine-1 (6H)-yl) methyl benzoate, ammonia water and an organic solvent for reaction to obtain a first intermediate; (2) mixing the first intermediate in the step (1), an esterification reagent and an organic solvent for esterification reaction to prepare a second intermediate; and (3) mixing the second intermediate obtained in the step (2) with N-methyl-N-isopropyl sulfamic acid and an organic solvent, and carrying out a reaction to prepare saflufenacil. The preparation method is high in yield, short in process, low in cost, environment-friendly and suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention relates to the field of herbicide preparation, and more specifically, to a method for preparing saflufenacil. Background Art

[0002] Safensulfuron is known as "the most successful new herbicide developed in more than 20 years" and represents a new level of broadleaf weed control. Safensulfuron has foliar contact and soil residual activity and can be transmitted bidirectionally in the plant body. It is mainly transmitted upward through the xylem and has the ability to transmit downward from the phloem, so that it can be distributed throughout the plant body and has a long-lasting effect. In addition, safensulfuron is safe for crops and provides a wide range of crop rotation options. It can effectively control more than 90 broadleaf weeds and has an inhibitory effect on grass weeds; safensulfuron is known for its rapid weed control effect, excellent low temperature resistance and low-dose use. Since its launch in 2009, safensulfuron has rapidly gained market recognition for its excellent control effect on resistant broadleaf weeds and its applicability to a variety of crops. In the past four years, it has become a product with sales of over US$100 million, and its current global annual sales have exceeded US$250 million.

[0003] According to relevant reports, there are two main methods for preparing saflufenacil:

[0004] The first method is the side chain first method, the specific equation is as follows:

[0005]

[0006] The method uses 2-chloro-4-fluorobenzoic acid as a raw material, and prepares a side chain amide structure through nitration and chlorination reaction, and then synthesizes the amide structure on the side chain with N-methyl-N-isopropylsulfonamide to obtain an intermediate N-(2-chloro-4-fluoro-5-amino-benzoyl)-N'-isopropyl-N'-methylformamide with a large molecular weight, and then reacts N-(2-chloro-4-fluoro-5-amino-benzoyl)-N'-isopropyl-N'-methylformamide with an intermediate 3-amino-4,4,4-trifluorocrotonic acid ethyl ester to synthesize a pyrimidine ring structure, and finally performs a methylation reaction to obtain benzylpyruvate. The international patent with publication number WO2006125746A1 published on May 18, 2006 and the US patent with publication number US2010105562A1 published on October 12, 2007 both use this method to prepare benzylpyruvate. It can be seen from the disclosures of the above two patents that dimethylated byproducts may be produced in the last step of the process of preparing saflufenacil. The presence of these byproducts often makes it relatively difficult to separate and purify the final product from the reaction mixture.

[0007] The second preparation method of saflufenacil is to first synthesize the pyrimidine ring structure. The specific reaction formula is as follows:

[0008]

[0009] This method uses 2-chloro-4-fluoro-benzoic acid as a raw material, first synthesizes a pyrimidine ring structure, synthesizes 2-chloro-4-fluoro-5-(1,2,3,6-tetrahydro-2,6-dioxy-4-trifluoromethylpyrimidine-1-yl)-benzoic acid, then methylates it, and finally synthesizes a side chain amide structure of methylated 2-chloro-4-fluoro-5-(1,2,3,6-tetrahydro-2,6-dioxy-4-trifluoromethylpyrimidine-1-yl)-benzoic acid and an intermediate N-methyl-N-isopropylsulfonamide to obtain benzenesulfonamide. Although this method avoids dimethylated by-products, it requires ester hydrolysis to be prepared into acyl chloride activation before condensation reaction can be carried out, which leads to an increase in the number of reaction steps. In addition, ester hydrolysis requires acidic system hydrolysis, and the hydrolysis process has a long reaction time, high energy consumption, and incomplete conversion, which increases the invisible production cost. The U.S. patent number US2016214945A1 published on September 18, 2014 provides Agricultural chemicals (a type of pesticide). The document uses N, N'-carbonyldiimidazole as a condensation agent to prepare amides. Although the preparation process is shortened, the yield of benzylsulfuron is only 47%, which is relatively low and the cost is too high, making it unsuitable for large-scale industrial production.

[0010] In order to solve the above problems, a Chinese patent with patent number CN113185467B announced on March 8, 2022 announced a method for preparing saflufenacil. This method uses an I-methyl intermediate as a base material at a certain temperature, and obtains the product saflufenacil through two-step reactions such as continuous chlorination and condensation. This new method can improve the yield of saflufenacil, but this method will produce more by-products during the production process, thereby increasing certain production costs.

[0011] Therefore, it is necessary to provide a method for preparing saflufenacil, which has the characteristics of high yield, short process, low cost and no by-product generation. Summary of the invention

[0012] In view of the problems existing in the prior art, the object of the present invention is to provide a method for preparing saflufenacil, which has the characteristics of high synthesis yield, short process, low cost, simple product separation and purification, and can realize industrial large-scale production.

[0013] To solve the above problems, the present invention adopts the following technical solutions.

[0014] A method for preparing saflufenacil comprises the following steps:

[0015] (1) mixing methyl 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoate, aqueous ammonia and an organic solvent for reaction to obtain a first intermediate;

[0016] (2) mixing the first intermediate in step (1), an esterification agent and an organic solvent to carry out an esterification reaction to prepare a second intermediate;

[0017] (3) mixing the second intermediate in step (2), N-methyl-N-isopropylaminosulfonic acid and an organic solvent, and reacting to prepare saflufenacil;

[0018] The reaction formula is as follows:

[0019]

[0020] Further, the first intermediate is 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzamide; the second intermediate is 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate.

[0021] Furthermore, in the step (1), the mass ratio of ammonia water to methyl 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoate is 0.5 to 2:1.

[0022] Furthermore, the organic solvent in step (1) is a water-soluble solvent, specifically one or a mixture of two or more of alcohols, tetrahydrofuran and dioxane;

[0023] The alcohol is methanol, ethanol or tert-butanol.

[0024] Furthermore, in the step (2), the molar ratio of the first intermediate to the esterification agent is 1:1 to 1.3.

[0025] Furthermore, in step (2), the esterification reagent is one or a mixture of two or more of oxalamide, phosgene and solid phosgene.

[0026] Furthermore, the organic solvent in step (2) is a water-insoluble solvent, and the water-insoluble solvent is one or a mixture of two or more of dichloromethane, dichloroethane, toluene and chlorobenzene.

[0027] Furthermore, in the step (3), the molar ratio of the second intermediate to N-methyl-N-isopropylaminosulfonic acid is 1 to 1.2:1.

[0028] Furthermore, the organic solvent in step (3) is a water-insoluble solvent, specifically one or a mixture of two or more of dichloromethane, dichloroethane, toluene and chlorobenzene.

[0029] Furthermore, the reaction temperature of step (1) is 50-55°C; and the reaction temperature of step (2) is 0-10°C.

[0030] Furthermore, in step (3), the reaction temperature is 0 to 100° C., and the reaction time is 5 to 6 hours.

[0031] The specific contents are as follows:

[0032] A method for preparing saflufenacil, the specific process is as follows:

[0033] S1: 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoic acid methyl ester is subjected to aminolysis in the presence of aqueous ammonia and an organic solvent to obtain 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzamide;

[0034] S2: dissolving the 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzamide prepared in step S1 in an organic solvent, and then adding an esterification agent dropwise to prepare a 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate solution;

[0035] S3: Dissolve N-methyl-N-isopropylaminosulfonic acid in an organic solvent, cool it down, then add dropwise the 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate solution prepared in step S2, heat and stir to obtain saflufenacil.

[0036] Furthermore, the organic solvent in step S1 is one or a mixture of two or more of alcohols, tetrahydrofuran and dioxane, and the alcohol is methanol, ethanol or tert-butanol.

[0037] Furthermore, the organic solvent in step S1 is preferably methanol.

[0038] Furthermore, in step S1, the mass ratio of ammonia water to methyl 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoate is 0.5 to 2:1.

[0039] Furthermore, in step S1, the mass ratio of aqueous ammonia to methyl 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoate is preferably 1:1.

[0040] Furthermore, the organic solvent in step S2 is a water-insoluble solvent, specifically one or a mixture of two or more of dichloromethane, dichloroethane, toluene and chlorobenzene.

[0041] Furthermore, in step S2, the organic solvent is preferably ethylene dichloride.

[0042] Furthermore, in step S2, the esterification reagent is one or a mixture of two or more of oxalyl chloride, phosgene and solid phosgene.

[0043] Furthermore, in step S2, the esterification reagent is preferably oxalyl chloride.

[0044] Furthermore, in step S2, the molar ratio of the esterification agent to 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzamide is 1 to 1.3:1.

[0045] Furthermore, in step S2, the molar ratio of the esterification agent to 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzamide is 1.1:1.

[0046] Furthermore, the reaction temperature in step S3 is 0 to 100°C.

[0047] Furthermore, the reaction temperature of step S3 is preferably 0-10°C and 50-60°C.

[0048] Furthermore, the reaction temperature of step S3 is preferably 0 to 10°C.

[0049] Furthermore, in step S3, the molar ratio of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate solution to N-methyl-N-isopropylaminosulfonic acid is 1 to 1.2:1.

[0050] Furthermore, in step S3, the molar ratio of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate solution to N-methyl-N-isopropylaminosulfonic acid is preferably 1.02:1.

[0051] Furthermore, the organic solvent in step S3 is a water-insoluble solvent, specifically one or a mixture of two or more of dichloromethane, dichloroethane, toluene and chlorobenzene.

[0052] Furthermore, in step S3, the organic solvent is preferably ethylene dichloride.

[0053] Compared with the prior art, the advantages of the present invention are:

[0054] 1. This scheme provides a method for preparing saflufenacil, which is based on methyl 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoate, and the final product saflufenacil is prepared by aminolysis, esterification and condensation. The preparation method has a short process, low cost, high yield and no obvious by-products, and is suitable for industrial large-scale production. DETAILED DESCRIPTION

[0055] Embodiment 1:

[0056] Step 1: 380.0g of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl) methyl benzoate was added to 500.0g of methanol and 380.0g of ammonia water with a mass concentration of 25%, and the temperature was raised to 50-55°C, stirred for 5-8h, and the raw material 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl) methyl benzoate content of ≤0.3% was considered as qualified for conversion by HPLC. Methanol was then removed under reduced pressure, the remaining mixture was collected and cooled to room temperature, filtered, rinsed with 100.0g of water and then dried to obtain 347.0g of white solid.

[0057] Step 2: Add the white solid in step 1 to 700.0g of dichloroethane, cool to 0-10°C, then control the temperature to drop 132.5g of oxalyl chloride at 0-10°C for 1-2h. After the dropwise addition is completed, continue to keep warm and stir at 0-10°C for 1h, then slowly heat to reflux and keep warm and stir for 4h. The white solid prepared in step 1 is detected by HPLC and the content is ≤0.2%, which is considered to be qualified. After the reaction is completed, 500.0 g of dichloroethane is distilled out at room temperature to remove excess oxalyl chloride (the boiling point of oxalyl chloride is 19° C., which is much lower than the boiling point of dichloroethane. Therefore, when 500.0 g of dichloroethane is distilled out, the oxalyl chloride has been completely removed); after the distillation is completed, the distillation bottom material is cooled to 40-50° C., and 300.0 g of dichloroethane is added to prepare a dichloroethane solution of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate.

[0058] Step 3: Take 142.0g of N-methyl-N-isopropylaminosulfonic acid and 200.0g of dichloroethane, mix and cool to 0-10°C, then control the temperature to 0-10°C, and drop the dichloroethane solution of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate prepared in step 2, and the dropwise addition time is 2-3h. After the dropwise addition is completed, slowly heat to 50-60°C, stir and react for 5-6h until HPLC detects that 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate is completely converted. After the conversion is complete, the temperature is lowered to 20-30°C, 10.0 g of saflufenacil seed crystals are added and stirred for 1 hour, then the temperature is further lowered to -5-0°C and stirred for 1 hour, filtered and dried to obtain 440.0 g of white saflufenacil solid with a purity of 98.0% and a total yield of 88.0%.

[0059] Embodiment 2:

[0060] Step 1: 380.0g of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl) methyl benzoate was added to 500.0g of ethanol and 380.0g of ammonia water with a mass concentration of 25%, and the mixture was heated to 50-55°C and stirred for 5-8h. The raw material 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl) methyl benzoate content of ≤0.3% was considered as qualified for conversion by HPLC. The ethanol was then removed under reduced pressure, and the remaining mixture was collected and cooled to room temperature, filtered, rinsed with 100.0g of water, and then dried to obtain 343.0g of white solid.

[0061] Step 2: Add the white solid in step 1 to 700.0g toluene, cool to 0-10°C, then control the temperature to drop 130.0g oxalyl chloride at 0-10°C for 1-2h. After the dropwise addition is completed, continue to keep warm and stir at 0-10°C for 1h, then slowly heat to reflux and keep warm and stir for 4h. The white solid prepared in step 1 is detected by HPLC. The content is ≤0.2%, which is considered to be qualified. After the reaction is completed, about 400.0 g of toluene is distilled out at room temperature to remove excess oxalyl chloride (the boiling point of oxalyl chloride is 19° C., which is much lower than the boiling point of toluene. Therefore, when 400.0 g of toluene is distilled out, the oxalyl chloride has been completely removed); after the distillation is completed, the distillation bottom material is cooled to 40-50° C., and 300.0 g of toluene is added to prepare a toluene solution of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate.

[0062] Step 3: Take 140.0g of N-methyl-N-isopropylaminosulfonic acid and 200.0g of toluene, mix and cool to 0-10°C, then control the temperature to 0-10°C, and drop the toluene solution of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate prepared in step 2, and add the solution for 2-3h. After the addition is completed, slowly heat to 50-60°C, stir and react for 5-6h until HPLC detects that 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate is completely converted. After the conversion is complete, the temperature is lowered to 20-30°C, 10.0 g of saflufenacil seed crystals are added and stirred for 1 hour, then the temperature is further lowered to -5-0°C and stirred for 1 hour, filtered and dried to obtain 425.0 g of white saflufenacil solid with a purity of 98.2% and a total yield of 85.0%.

[0063] Embodiment 3:

[0064] Step 1: 380.0g of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl) methyl benzoate was added to 500.0g of tert-butyl alcohol and 380.0g of ammonia water with a mass concentration of 25%, and the mixture was heated to 50-55°C and stirred for 5-8h. The raw material 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl) methyl benzoate content of ≤0.3% was considered as qualified for conversion by HPLC. The tert-butyl alcohol was then removed under reduced pressure, and the remaining mixture was collected and cooled to room temperature, filtered, rinsed with 100.0g of water, and then dried to obtain 345.0g of white solid.

[0065] Step 2: Add the white solid in step 1 to 700.0g of dichloroethane, cool to 0-10°C, then control the temperature to drop 132.5g of oxalyl chloride at 0-10°C for 1-2h. After the dropwise addition is completed, continue to keep warm and stir at 0-10°C for 1h, then slowly heat to reflux and keep warm and stir for 4h. The white solid prepared in step 1 is detected by HPLC and the content is ≤0.2%, which is considered to be qualified. After the reaction is completed, about 500.0 g of dichloroethane is distilled out at room temperature to remove excess oxalyl chloride (the boiling point of oxalyl chloride is 19° C., which is much lower than the boiling point of dichloroethane. Therefore, when 500.0 g of dichloroethane is distilled out, the oxalyl chloride has been completely removed); after the distillation is completed, the distillation bottom material is cooled to 40-50° C., and 300.0 g of dichloroethane is added to prepare a dichloroethane solution of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate.

[0066] Step 3: Take 142.0g of N-methyl-N-isopropylaminosulfonic acid and 200.0g of dichloroethane, mix and cool to 0-10°C, then control the temperature to 0-10°C, and drop the dichloroethane solution of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate prepared in step 2, and add the solution for 2-3h. After the addition is completed, slowly heat to 50-60°C, stir and react for 5-6h until HPLC detects that 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoyl isocyanate is completely converted. After the conversion is complete, the temperature is lowered to 20-30°C, 10.0 g of saflufenacil seed crystals are added and stirred for 1 hour, then the temperature is further lowered to -5-0°C and stirred for 1 hour, filtered and dried to obtain 431.5 g of white saflufenacil solid with a purity of 98.4% and a total yield of 86.3%.

Claims

1. A method for preparing saflufenacil, characterized in that: The following steps are included: (1) mixing methyl 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoate, aqueous ammonia and an organic solvent for reaction to obtain a first intermediate; (2) mixing the first intermediate in step (1), an esterification agent and an organic solvent to carry out an esterification reaction to prepare a second intermediate; (3) mixing the second intermediate in step (2), N-methyl-N-isopropylaminosulfonic acid and an organic solvent, and reacting to prepare saflufenacil; The reaction equation is as follows, 2. The method for preparing saflufenacil according to claim 1, characterized in that: In the step (1), the mass ratio of ammonia water to methyl 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-2,3-dihydropyrimidin-1(6H)-yl)benzoate is 0.5 to 2:

1.

3. The method for preparing saflufenacil according to claim 1, characterized in that: The organic solvent in step (1) is a water-soluble solvent, and the organic solvent is one or a mixture of two or more of alcohols, tetrahydrofuran and dioxane; The alcohol is methanol, ethanol or tert-butanol.

4. The method for preparing saflufenacil according to claim 1, characterized in that: In the step (2), the molar ratio of the first intermediate to the esterification agent is 1:1 to 1.

3.

5. The method for preparing saflufenacil according to claim 1, characterized in that: In the step (2), the esterification reagent is one or a mixture of two or more of oxalyl chloride, phosgene and solid phosgene.

6. The method for preparing saflufenacil according to claim 1, characterized in that: The organic solvent in step (2) is a water-insoluble solvent, and the water-insoluble solvent is one or a mixture of two or more of dichloromethane, dichloroethane, toluene and chlorobenzene.

7. The method for preparing saflufenacil according to claim 1, characterized in that: In the step (3), the molar ratio of the second intermediate to N-methyl-N-isopropylaminosulfonic acid is 1 to 1.2:

1.

8. The method for preparing saflufenacil according to claim 1, characterized in that: The organic solvent in step (3) is a water-insoluble solvent, and the water-insoluble solvent is one or a mixture of two or more of dichloromethane, dichloroethane, toluene and chlorobenzene.

9. The method for preparing saflufenacil according to claim 1, characterized in that: The reaction temperature of step (1) is 50-55°C; the reaction temperature of step (2) is 0-10°C.

10. The method for preparing saflufenacil according to claim 1, characterized in that: The reaction temperature of step (3) is 0-100° C., and the reaction time is 5-6 h.

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