Synthesis method of dithiobac-methyl intermediate
By using 4-chloro-2-fluoroaniline and ethyl trifluoroacetoacetate instead of highly toxic and expensive raw materials, and cyclization and methylation reactions to synthesize fluoropythiothioester intermediates, the problems of operational risk and cost are solved, and safety and economical improvements are achieved.
Patent Information
- Application Number
- CN202510235832.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-28
- Publication Date
- 2025-07-08
AI Technical Summary
The starting material ethyl chloroformate used in the existing fluoropythiothioester intermediate synthesis method is highly toxic and expensive, resulting in high operational risk and high production costs, which is not suitable for large-scale industrial production.
4-chloro-2-fluoroaniline and ethyl trifluoroacetoacetate are used as starting materials to synthesize fluoropythiothioester intermediates through condensation, cyclization and methylation reactions, avoid the use of highly drugs and expensive raw materials, and use low-priced cyanate and phase transfer catalysts.
It improves operational safety, reduces production costs, and is suitable for large-scale industrial production.
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of the synthesis of herbicide intermediates, and particularly relates to a method for synthesizing an intermediate of tiafenacil. Background Art
[0002] Tiafenacil is a new type of uracil non-selective herbicide jointly developed by FMC Korea Co., Ltd., the Korea Research Institute of Chemical Technology, etc. It is a new type of herbicide that inhibits protoporphyrinogen oxidase (PPO). It is mainly used in crop fields such as soybeans, rapeseed, rice, corn, wheat, etc., and also in orchards and non-cultivated lands to control broad-leaved weeds and gramineous weeds, and can control weeds resistant to herbicides such as glyphosate; it can also be used as a defoliant for cotton, fruit trees, etc.
[0003] 3-(4-Chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione [CAS No. 114136-66-2, molecular formula C 12 H7ClF4N2O2, molecular weight 322.64] is an important intermediate for synthesizing tiafenacil.
[0004] The existing synthesis method of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione uses 4-chloro-2-fluoroaniline and ethyl chloroformate as starting materials. First, the intermediate ethyl N-(4-chloro-2-fluorophenyl)carbamate is obtained through a condensation reaction, and then it reacts with ethyl 3-amino-4,4,4-trifluorocrotonate through a cyclization reaction to obtain the intermediate 3-(4-chloro-2-fluorophenyl)-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione [CAS No. 114136-63-9, molecular formula C 11 H5ClF4N2O2, molecular weight 308.62], and finally it reacts with dimethyl sulfate through a methylation reaction to obtain 3-(4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione.
[0005] The specific synthesis route is as follows: .
[0006] The disadvantages of this synthesis route are: (1) The starting material ethyl chloroformate is a highly toxic substance, and the operation is relatively dangerous; (2) The raw material ethyl 3-amino-4,4,4-trifluorocrotonate is expensive, resulting in a relatively high production cost. Summary of the Invention
[0007] The purpose of the present invention is to solve the above problems and provide a method for synthesizing an intermediate of tiafenacil with high operation safety, low production cost and suitable for large-scale industrial production.
[0008] The technical solution for achieving the object of the present invention is as follows: A method for synthesizing an intermediate of fluthiacet-methyl, comprising the following steps: ① Using 4-chloro-2-fluoroaniline and ethyl trifluoroacetoacetate as starting materials, first obtaining a first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide through a condensation reaction; ② The first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide obtained in step ① reacts with cyanate through a cyclization reaction to obtain a second intermediate 3-(4-chloro-2-fluorophenyl)-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione; ③ The second intermediate 3-(4-chloro-2-fluorophenyl)-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione obtained in step ② reacts with a methylation reagent through a methylation reaction to obtain an intermediate of fluthiacet-methyl, 3-(4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione.
[0009] The synthesis route is as follows: .
[0010] In the condensation reaction of step ①, the molar ratio of the 4-chloro-2-fluoroaniline to the ethyl trifluoroacetoacetate is 1:1 to 1:1.5.
[0011] The condensation reaction of step ① is carried out in the presence of a base; the molar ratio of the 4-chloro-2-fluoroaniline to the base is 1:0.1 to 1:1.
[0012] The base is one of sodium bicarbonate, sodium carbonate, sodium alkoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, and preferably sodium bicarbonate.
[0013] The condensation reaction of step ① is carried out in the presence of a first solvent; the first solvent is one of xylene, toluene, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, and preferably xylene.
[0014] The cyclization reaction of step ② is carried out in the presence of the first solvent.
[0015] In the cyclization reaction of step ②, the cyanate is sodium cyanate or potassium cyanate; the molar ratio of the first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide to the cyanate is 1:1 to 1:4.
[0016] The cyclization reaction in step ② is carried out in the presence of acetic acid; the molar ratio of the first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide to the acetic acid is 1:5 to 1:20.
[0017] The cyclization reaction in step ② is carried out in the presence of a phase transfer catalyst; the weight ratio of the first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide to the phase transfer catalyst is 1:0.005 to 1:0.02.
[0018] The phase transfer catalyst is one of tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, benzyltriethylammonium chloride (TEBA), trioctylmethylammonium chloride, 18-crown-6, 15-crown-5, cyclodextrin, polyethylene glycol; preferably one of tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, benzyltriethylammonium chloride (TEBA), trioctylmethylammonium chloride; more preferably tetrabutylammonium bromide (TBAB).
[0019] The methylation reaction in step ③ is a conventional method in the art, and the methylation reagent is preferably dimethyl sulfate.
[0020] The positive effects of the present invention are as follows: The synthesis method of the present invention uses ethyl trifluoroacetoacetate to replace ethyl chloroformate to carry out a condensation reaction with 4-chloro-2-fluoroaniline. This can not only avoid the use of the highly toxic ethyl chloroformate, thus greatly improving the operation safety, but also the first intermediate obtained by condensation can be cyclized with a low-cost cyanate to obtain the second intermediate 3-(4-chloro-2-fluorophenyl)-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione, thereby avoiding the use of expensive ethyl 3-amino-4,4,4-trifluorocrotonate, greatly reducing the production cost, and being suitable for large-scale industrial production. Detailed implementation mode
[0021] (Example 1) The synthesis method of the fluthiacet-methyl intermediate 3-(4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione in this example has the following steps: ① Add 130 g of xylene, 29.1 g of 4-chloro-2-fluoroaniline (0.2 mol), and 8.4 g of sodium bicarbonate (0.1 mol) to a 500 mL reaction flask. Stir and heat up to 110 °C, and control the temperature at 110 ± 5 °C to dropwise add 46 g of ethyl trifluoroacetoacetate (0.25 mol). Finish dropping in about 2 h. After dropping, keep the temperature at 110 °C ± 5 °C for heat preservation reaction for 8 h, and distill out the generated ethanol during the reaction.
[0022] After the reaction is completed, cool down to below 20 °C, precipitate solids, filter by suction, wash with water, and dry to obtain 52.7 g of white solid N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide, with a yield of 92.9% and an HPLC purity of 99.0%.
[0023] ② Add 210 g of xylene, 52.7 g of N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide (0.186 mol), 0.5 g of tetrabutylammonium bromide, and 30.1 g of potassium cyanate (0.372 mol) to a 1000 mL reaction flask. Heat up to 40 °C, dropwise add 25 g of acetic acid, finish dropping in 30 min, then heat up to 85 °C, and dropwise add 70 g of acetic acid, finish dropping in 2 h. After dropping, react at 85 °C for 7 h.
[0024] After the reaction is completed, cool down to 25 °C, dropwise add 150 g of water, precipitate white solids, stir at room temperature for 1 h, filter by suction. After the filter cake is washed with water and dried, obtain white solids. Layer the filtrate. There is a small amount of product in the upper xylene layer. The white solids and the xylene layer are directly used for the next methylation reaction.
[0025] ③ Add the white solids and the xylene layer obtained in step , 25.4 g of potassium carbonate, 0.5 g of tetrabutylammonium bromide, and 52 g of acetone to a 500 mL reaction flask. Heat up to 40 °C, control the temperature at 40 - 45 °C to dropwise add 25.2 g of dimethyl sulfate (0.2 mol), with slight exotherm, finish dropping in about 2 h. After dropping, keep the temperature at 40 - 45 °C for heat preservation reaction for 5 h.
[0026] After the reaction is completed, add 300 g of water, stir for 10 min, layer. Extract the aqueous layer once with 50 g of xylene, combine the organic layers, wash once with 200 g of water. Recover xylene by solvent stripping from the organic layer to obtain yellow solids. Finally, recrystallize with 120 g of ethanol to obtain 51.2 g of white crystals, with an HPLC purity of 98.5% and a two-step reaction yield of 85.4%.
[0027] (Examples 2 - 7) The preparation methods of each example are for the first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide, which are basically the same as that of Example 1, and the differences are shown in Table 1.
[0028] Table 1 Ethyl trifluoroacetoacetate Base used in the condensation reaction Weight Yield Purity Example 1 0.25 mol 0.1 mol sodium bicarbonate 52.7g 92.9% 99.0% Example 2 0.25 mol 0.05 mol sodium bicarbonate 50.3g 88.7% 98.2% Example 3 0.25 mol 0.15 mol sodium bicarbonate 52.9g 93.3% 99.1% Example 4 0.25 mol 0.1 mol sodium hydroxide 49.5g 87.3% 98.4% Example 5 0.25 mol 0.1 mol potassium hydroxide 48.8g 86.1% 98.1% Example 6 0.22 mol 0.1 mol sodium bicarbonate 51.4g 90.7% 98.8% Example 7 0.28 mol 0.1 mol sodium bicarbonate 53.1g 93.7% 99.2%
[0029] (Examples 8 to 13) For each of the examples, the method for preparing the intermediate of fluthiacet-methyl, 3-(4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione, from the first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide was substantially the same as that of Example 1, except for the types and amounts of cyanate and phase transfer catalyst in step ②. See Table 2 for details.
[0030] Table 2 Cyanate Phase transfer catalyst Weight Yield Purity Example 1 30.1 g potassium cyanate, 2 eq 0.5 g tetrabutylammonium bromide 51.2g 85.4% 98.5% Example 8 22.6 g potassium cyanate, 1.5 eq 0.5 g tetrabutylammonium bromide 49.7g 82.9% 98.2% Example 9 45.2 g potassium cyanate, 3 eq 0.5 g tetrabutylammonium bromide 51.8g 86.4% 98.6% Example 10 24.2 g sodium cyanate, 2 eq 0.5 g tetrabutylammonium bromide 50.5g 84.2% 98.3% Example 11 30.1 g potassium cyanate, 2 eq 0.5 g tetrabutylammonium chloride 50.2g 83.7% 98.2% Example 12 30.1 g potassium cyanate, 2 eq 0.5 g dodecyltrimethylammonium chloride 49.8g 83.1% 98.0% Example 13 30.1 g potassium cyanate, 2 eq 0.5 g benzyltriethylammonium chloride 51.5g 85.9% 98.8%
Claims
1. A synthetic method of the intermediate of fluthiacet-methyl, characterized in that It has the following steps: ① Using 4-chloro-2-fluoroaniline and ethyl trifluoroacetoacetate as starting materials, first obtain the first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide through a condensation reaction; ② The first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide obtained in step ① reacts with cyanate through a cyclization reaction to obtain the second intermediate 3-(4-chloro-2-fluorophenyl)-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione; ③ The second intermediate 3-(4-chloro-2-fluorophenyl)-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione obtained in step ② reacts with a methylation reagent through a methylation reaction to obtain the fluthiacet-methyl intermediate 3-(4-chloro-2-fluorophenyl)-1-methyl-6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione.
2. The synthesis method of the intermediate of fluthiacet-methyl according to claim 1, wherein: In the condensation reaction of step ①, the molar ratio of the 4-chloro-2-fluoroaniline to the ethyl trifluoroacetoacetate is 1:1 to 1:1.
5.
3. The synthesis method of the fluoroxypyr-ethyl intermediate according to claim 1, characterized in that: The condensation reaction of step ① is carried out in the presence of a base; the molar ratio of the 4-chloro-2-fluoroaniline to the base is 1:0.1 to 1:
1.
4. The synthesis method of the fluoroxypyr-ethyl intermediate according to claim 3, characterized in that: The base is one of sodium bicarbonate, sodium carbonate, sodium alkoxide, sodium hydroxide, potassium hydroxide, and lithium hydroxide.
5. The synthesis method of the fluoropyrimidat intermediate according to claim 1, characterized in that: The condensation reaction of step ① is carried out in the presence of a first solvent; the first solvent is one of xylene, toluene, 1,4-dioxane, acetonitrile, and N,N-dimethylformamide.
6. The synthetic method of the fluoropyrimidat intermediate according to claim 5, characterized in that: The cyclization reaction of step ② is carried out in the presence of the first solvent.
7. The synthesis method of the fluoroxypyr-ethyl intermediate according to claim 1, characterized in that: In the cyclization reaction of step ②, the cyanate is sodium cyanate or potassium cyanate; the molar ratio of the first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide to the cyanate is 1:1 to 1:
4.
8. The synthesis method of the fluoroglycofen-ethyl intermediate according to claim 1, characterized in that: The cyclization reaction of step ② is carried out in the presence of acetic acid; the molar ratio of the first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide to the acetic acid is 1:5 to 1:
20.
9. The synthetic method of the fluoroxypyr-ethyl intermediate according to claim 1, characterized in that: The cyclization reaction of step ② is carried out in the presence of a phase transfer catalyst; the molar ratio of the first intermediate N-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-oxobutanamide to the phase transfer catalyst is 1:0.005 to 1:0.
015.
10. The synthesis method of the fluoroxypyr-butafenacil intermediate according to claim 9, characterized in that: The phase transfer catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, benzyltriethylammonium chloride, trioctylmethylammonium chloride, 18-crown-6, 15-crown-5, cyclodextrin, and polyethylene glycol.