Synthesis method of dithiobac-methyl

Abstract

The synthesis method comprises the following steps: reacting a sulfonyl chloride intermediate with a red phosphorus-iodine-acetic acid reduction system to obtain an ethyl sulfate intermediate, and reacting the ethyl sulfate intermediate with 3-(2-chloropropionamido) methyl propionate in the presence of an organic alkali and an organic solvent to obtain the dithiobac-methyl. According to the synthesis method disclosed by the invention, the ethyl sulfate intermediate obtained by reducing the sulfonyl chloride intermediate directly reacts with the methyl 3-(2-chloropropionamido) propionate to obtain the dithiobac-methyl, so that the acidolysis step is reduced, the operation process is greatly simplified, the defect that disulfide impurities are easily generated by a sulfydryl intermediate is overcome, and the yield of the dithiobac-methyl is improved. And the fluopyrithiobac-methyl with relatively high purity can be obtained.

Description

Technical Field

[0001] The invention belongs to the technical field of herbicide synthesis, and particularly relates to a method for synthesizing fluazifop-butyl. Background Art

[0002] Fluamithiosulfuron (English name Tiafenacil) is a new type of uracil non-selective herbicide jointly developed by Fuam Hannong Co., Ltd., Korea Institute of Chemical Technology, etc. It is a new type of protoporphyrinogen oxidase (PPO) inhibitor herbicide. It is mainly used in crop fields such as soybeans, rapeseed, rice, corn, and wheat, as well as in orchards and non-arable land to control broadleaf weeds and grass 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] The existing synthesis methods of fluazifop-butyl are basically to obtain the product by nucleophilic substitution reaction of 3-(4-chloro-2-fluoro-5-mercaptophenyl)-1-methyl-6-trifluoromethyl-1H-pyrimidine-2,4-dione (hereinafter referred to as the thiol intermediate) and 3-(2-chloropropionylamino) propionic acid methyl ester [see Example 7 of Chinese patent document CN102203071A]. The thiol intermediate is basically to obtain the product by reaction of 2-chloro-4-fluoro-5-(3,6-dihydro-3-methyl-2,6-dioxy-4-trifluoromethyl-1(2H)-pyrimidinyl)benzenesulfonyl chloride (hereinafter referred to as the sulfonyl chloride intermediate). One method is to reduce the product by red phosphorus-iodine-acetic acid system, and then to obtain the thiol intermediate by acid hydrolysis with hydrochloric acid [see Example 1 of Chinese patent document CN103539748A].

[0004] The synthetic route of the above method is shown in the following formula: .

[0005] The disadvantages of this method are that the thiol intermediate has poor stability and disulfide impurities will be generated during storage. In addition, the nucleophilic substitution reaction between the thiol intermediate and 3-(2-chloropropionamido) methyl propionate will also produce a certain amount of disulfide impurities, resulting in low product purity.

[0006] The structural formula of the disulfide impurity is as follows: . Summary of the invention

[0007] The object of the present invention is to solve the above-mentioned problem and provide a method for synthesizing fluazifop-butyl which can avoid the generation of disulfide impurities and thus has a higher product purity.

[0008] The technical solution to achieve the purpose of the present invention is: a method for synthesizing fluazifop-butyl, comprising the following steps: ①2-Chloro-4-fluoro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl)benzenesulfonyl chloride (hereinafter referred to as sulfonyl chloride intermediate) reacts with red phosphorus-iodine-acetic acid reduction system to obtain S-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-phenyl] ethyl sulfate (hereinafter referred to as ethyl sulfate intermediate).

[0009] ② The S-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidine-1(2H)-phenyl] ethyl sulfate obtained in step ① is reacted with methyl 3-(2-chloropropionamido)propionate in the presence of an organic base and an organic solvent to obtain fluazifop-butyl.

[0010] The reaction formula is as follows: .

[0011] In the above step ①, the molar ratio of the red phosphorus to the sulfonyl chloride intermediate is 1:1 to 4:1.

[0012] In the above step ①, the molar ratio of the iodine to the sulfonyl chloride intermediate is 0.01:1 to 0.05:1.

[0013] In the above step ①, the molar ratio of the acetic acid to the sulfonyl chloride intermediate is 5:1 to 20:1.

[0014] The reaction temperature of the above step ① is reflux temperature.

[0015] In the above step ②, the molar ratio of the methyl 3-(2-chloropropionamido)propionate to the ethyl sulfate intermediate is 0.8:1 to 1.2:1.

[0016] In the above step ②, the organic base is sodium methoxide, sodium ethoxide or sodium tert-butoxide, preferably sodium methoxide.

[0017] In the above step ②, the molar ratio of the organic base to the ethylsulfate intermediate is 1:1 to 4:1.

[0018] In the above step ②, the organic solvent is acetonitrile.

[0019] The reaction temperature of the above step ② is reflux temperature.

[0020] The present invention has positive effects: the synthesis method of the present invention directly uses the ethyl sulfate intermediate obtained by reducing the sulfonyl chloride intermediate to react with 3-(2-chloropropionamido) propionate methyl ester to obtain fluazifop-butyl, which not only reduces the acid hydrolysis step, thereby greatly simplifying the operation process, but also avoids the disadvantage that the thiol intermediate is prone to produce disulfide impurities, and can obtain fluazifop-butyl with higher purity. DETAILED DESCRIPTION

[0021] (Example 1) This embodiment is a method for preparing an ethylsulfate intermediate, and the reaction formula is as follows: .

[0022] The specific method is as follows: In a 500 mL four-necked flask, 21.1 g of sulfonyl chloride intermediate (0.05 mol), 3.1 g of red phosphorus (0.1 mol), 0.25 g of iodine (0.001 mol) and 30 g of acetic acid (0.5 mol) were added, and the temperature was raised to reflux for reaction for 8 h.

[0023] After the reaction was completed, the mixture was cooled to room temperature and filtered. 100 mL of water and 200 mL of toluene were added to the filtrate, and the mixture was stirred for 20 min. The mixture was allowed to stand for stratification. The organic layer was washed once with water and the solvent was removed to obtain 18.4 g of ethyl sulfate intermediate with a purity of 97.4% and a yield of 92.6%.

[0024] (Example 2 to Example 4) The preparation methods of each embodiment are basically the same as that of embodiment 1, and the differences are shown in Table 1.

[0025] Table 1 Example 1 Example 2 Example 3 Example 4 Four-mouth bottle 500mL 500mL 500mL 2L Sulfonyl chloride intermediate 21.1g, 0.05mol 21.1g, 0.05mol 21.1g, 0.05mol 105.3g, 0.25mol Red Phosphorus 3.1g, 0.1mol 2.48g, 0.08mol 4.65g, 0.15mol 15.5g, 0.5mol iodine 0.25g, 0.001mol 0.25g, 0.001mol 0.51g、0.002mol 1.27g, 0.005mol acetic acid 30g, 0.5mol 24g, 0.4mol 32g, 0.7mol 150g, 2.5mol Heating reflux reaction time 8h 7.5h 8.5h 12h Post-treatment water 100mL 100mL 100mL 500mL Toluene for post-treatment 200mL 200mL 200mL 1L Ethylsulfate intermediate weight 18.4g 18.0g 18.2g 93.2g Purity of ethylsulfate intermediate 97.4% 97.0% 97.4% 97.5% Yield 92.6% 90.6% 91.6% 94.0%

[0026] (Example 5) This embodiment is a method for preparing fluazifop-butyl, and the reaction formula is as follows: .

[0027] The method is as follows: In a 250 mL four-necked flask, 19.8 g of the ethyl sulfate intermediate obtained in Example 4 (0.05 mol), 9.7 g of methyl 3-(2-chloropropionamido)propionate (0.05 mol), 18 g (0.1 mol) of a 30 wt% sodium methoxide-methanol solution and 50 mL of acetonitrile were added, and the temperature was raised to reflux and stirred for reaction for 6 h.

[0028] After the reaction was completed, the mixture was cooled to room temperature, 50 mL of water and 50 mL of dichloromethane were added, stirred for 10 min, and allowed to stand for stratification. 50 mL of water was added to the organic layer, stirred for 10 min, and allowed to stand for stratification. After the solvent was removed from the organic layer, 30 mL of isopropanol was added, stirred and heated until the solution was clear, then the temperature was slowly lowered for crystallization, filtered, and dried to obtain 18.0 g of white solid fluazifop-butyl with HPLC purity of 98.0% and a yield of 70.5%.

[0029] (Example 6 to Example 8) The preparation methods of each embodiment are basically the same as that of embodiment 5, and the differences are shown in Table 2.

[0030] Table 2 Example 5 Example 6 Example 7 Example 8 Organic base 30wt% sodium methoxide-methanol solution 18g, 0.1mol 30wt% sodium methoxide-methanol solution 14.4g, 0.08mol 30wt% sodium methoxide-methanol solution 27g, 0.15mol 21wt% sodium ethoxide-ethanol solution 32.4g, 0.1mol Fluazifop-butyl 18.0g 17.6g 18.3g 17.2g HPLC purity 98.0% 98.0% 98.2% 97.8% Yield 70.5% 68.9% 71.6% 67.3%

Claims

1. A method for synthesizing fluazifop-butyl, comprising the following steps: ① 2-Chloro-4-fluoro-5-(3,6-dihydro-3-methyl-2,6-dioxy-4-trifluoromethyl-1(2H)-pyrimidinyl)benzenesulfonyl chloride reacts with red phosphorus-iodine-acetic acid reduction system to obtain S-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxy-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-phenyl] ethyl sulfate; ② The S-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidine-1(2H)-phenyl] ethyl sulfate obtained in step ① is reacted with methyl 3-(2-chloropropionamido)propionate in the presence of an organic base and an organic solvent to obtain fluazifop-butyl.

2. The method for synthesizing fluazifop-butyl according to claim 1, characterized in that: In the above step ①, the molar ratio of the red phosphorus to the sulfonyl chloride intermediate is 1:1 to 4:

1.

3. The method for synthesizing fluazifop-butyl according to claim 1, characterized in that: In the above step ①, the molar ratio of the iodine to the sulfonyl chloride intermediate is 0.01:1 to 0.05:

1.

4. The method for synthesizing fluazifop-butyl according to claim 1, characterized in that: In the above step ①, the molar ratio of the acetic acid to the sulfonyl chloride intermediate is 5:1 to 20:

1.

5. The method for synthesizing fluazifop-butyl according to claim 1, characterized in that: The reaction temperature of the above step ① is reflux temperature.

6. The method for synthesizing fluazifop-butyl according to claim 1, characterized in that: The reaction temperature of the above step ② is reflux temperature.

7. The method for synthesizing fluazifop-butyl according to claim 1, characterized in that: In the above step ②, the organic solvent is acetonitrile.

8. The method for synthesizing fluazifop-butyl according to claim 1, characterized in that: The molar ratio of the methyl 3-(2-chloropropionamido)propionate to the ethyl sulfate intermediate is 0.8:1 to 1.2:

1.

9. The method for synthesizing fluazifop-butyl according to any one of claims 1 to 8, characterized in that: In the above step ②, the organic base is sodium methoxide, sodium ethoxide or sodium tert-butoxide.

10. The method for synthesizing fluazifop-butyl according to claim 9, characterized in that: In the above step ②, the molar ratio of the organic base to the ethylsulfate intermediate is 1:1 to 4:1.