Preparation method of oxamate intermediate

Abstract

The invention belongs to the field of chemical engineering and pesticides, and particularly relates to a preparation method of a fluonamate intermediate, 3, 5-dichloro-2, 6-difluoro-4-aminopyridine and (R)-methyl lactate are used as raw materials, and the fluonamate intermediate is generated through a nucleophilic substitution reaction. According to the present invention, with the easily available raw materials, the simple and easily-controlled process, the high yield and the high ee value can be obtained;

Description

[0001] The invention belongs to the field of chemical industry and pesticides, and relates to a method for preparing a fluazifop-butyl intermediate Background Art

[0002] Fluchloraminopyr-tefuryl, English name: Fluchloraminopyr-tefuryl, is a new type of non-selective herbicide of pyridyloxycarboxylic acid independently developed by Qingyuan Agro-Crown in 2019. In April 2022, fluchloraminopyr-tefuryl was first registered in Cambodia. In June 2024, fluchloraminopyr-tefuryl 98% technical (only for export to Cambodia) was registered in China. It can be used for weeding in non-cultivated land such as barren mountains, slopes, roadsides, ditches, etc., and can also be used for weeding between rows in some orchards. It is mainly used to control annual grass weeds such as barnyard grass, crabgrass, chinensis, Setaria viridis, as well as annual and perennial broad-leaved weeds such as ramie, herb, Bidens pilosa, Erigeron canina, Commelina, Erigeron chinensis, Sonchus endive, Chickweed, Equisetum arvense, bindweed, Polygonum aviculare, Humulus, Artemisia selengensis, Shepherd's purse, Gnaphalium sphaerocephalum, Gnaphalium sphaerocephalum, and Chickweed. It also has preventive effects on sedge weeds.

[0003] The preparation method of fluazifop-butyl reported in the patent is mainly as follows: 4-amino-3,5-dichloro-6-fluoropyridin-2-ol potassium salt and ( S )-2-bromopropionic acid methyl ester as raw material, through three steps of reaction to obtain fluazifop-butyl, the synthesis route is as follows:

[0004] This route is through potassium salt and ( S )-2-bromopropionic acid methyl ester undergoes nucleophilic substitution, followed by hydrolysis and esterification to obtain fluazifop-butyl. This process requires the use of the more expensive ( S )-2-bromopropionic acid methyl ester, and pre-made potassium salt, the cost is high and not conducive to industrial production.

[0005] Through the analysis of the process route, it can be seen that the structural formula is The fluazifop-butyl intermediate is the key intermediate for the synthesis of fluazifop-butyl.

[0006] Therefore, the present application provides a method for preparing a fluazifop-butyl intermediate. Summary of the invention

[0007] The object of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing a fluazifop-butyl intermediate. R )-methyl lactate and 3,5-dichloro-2,6-difluoropyridin-4-amine were used as raw materials to obtain the intermediate of fluazifop-butyl.

[0008] To achieve the above object, the present invention is implemented by adopting the following technical solutions: The present invention provides a preparation method of a flucarbazone-methyl intermediate, comprising the following steps: Using ( R )-methyl lactate and 3,5-dichloro-2,6-difluoropyridin-4-amine as raw materials, a nucleophilic substitution reaction occurs under alkaline conditions to generate the flucarbazone-methyl intermediate.

[0009] The structural formula of the flucarbazone-methyl intermediate is as follows:

[0010] Further, the reaction route of the flucarbazone-methyl intermediate is as follows:

[0011] The reaction is carried out in the presence of a basic substance, and the basic substance is an organic base or an inorganic base. It is selected from any one or a combination of sodium bicarbonate, potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, N , N -diisopropylethylamine, 2,6-dimethylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, and the preferred base is sodium tert-butoxide.

[0012] Further, the solvent is selected from dimethyl sulfoxide, N , N -dimethylformamide, 1,4-dioxane, tetrahydrofuran, ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, ethylbenzene, or any combination thereof, and the preferred solvent is tetrahydrofuran.

[0013] Further, the temperature is selected from 0 to 120 °C, and the preferred temperature is 80 °C.

[0014] Further, the reaction time is selected from 0.5 to 24 h, and the preferred reaction time is 10 h.

[0015] Further, the equivalent ratio of 3,5-dichloro-2,6-difluoropyridin-4-amine to ( R )-methyl lactate is selected from 1 to 3, and the preferred equivalent ratio is 1:1.5.

[0016] Further, the base equivalent ratio is 1 to 3 (relative to ( R )-methyl lactate), and the preferred equivalent ratio is 1:1.5.

[0017] Further, the amount of the solvent is 0.01 to 1 M (relative to 3,5-dichloro-2,6-difluoropyridin-4-amine), and the preferred amount of the solvent is 0.2 M.

[0018] Specific Embodiment of the Example Example 1: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, then dichloromethane (5.0 mL) was added and stirred evenly. Subsequently, ( R )-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.) were added. Finally, a reflux condenser was added and the mixture was stirred at 100 o °C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized from petroleum ether and ethyl acetate to obtain the target compound with a yield of 89%.

[0019] Example 2: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, then dichloromethane (5.0 mL) was added and stirred evenly. Subsequently, ( R )-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.) were added. Finally, a reflux condenser was added and the mixture was stirred at 40 o °C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized from petroleum ether and ethyl acetate to obtain the target compound with a yield of 64%.

[0020] Example 3: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, then dichloromethane (5.0 mL) was added and stirred evenly. Subsequently, ( R )-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.) were added. Finally, a reflux condenser was added and the mixture was stirred at 80 o °C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized from petroleum ether and ethyl acetate to obtain the target compound with a yield of 72%.

[0021] Example 4: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, and then 1,4-dioxane (5.0 mL) was added and stirred evenly. Subsequently, ([[]] R [[]])-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.) were added. Finally, a condenser reflux tube was added and the mixture was stirred at 100[[]] o [[]]°C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 55%. R )-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.), and finally a condenser reflux tube was added and stirred at 100[[]] o [[]]°C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 55%. o C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 55%.

[0022] Example 5: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, and then tetrahydrofuran (5.0 mL) was added and stirred evenly. Subsequently, ([[]] R [[]])-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.) were added. Finally, a condenser reflux tube was added and stirred at 80[[]] o [[]]°C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 84%. R )-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.), and finally a condenser reflux tube was added and stirred at 80[[]] o [[]]°C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 84%. o °C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 84%.

[0023] Example 6: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, and then N,N-dimethylformamide (5.0 mL) was added and stirred evenly. Subsequently, ([[]] R [[]])-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.) were added. Finally, a condenser reflux tube was added and stirred at 80[[]] o [[]]°C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 68%. R )-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.), and finally a condenser reflux tube was added and stirred at 80[[]] o [[]]°C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 68%. o °C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 68%.

[0024] Example 7: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, and then 1,4-dioxane (5.0 mL) was added and stirred evenly. Subsequently, ([[]] R [[]])-methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.) were added. Finally, a condenser reflux tube was added and stirred at 100[[]] o [[]]°C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized with petroleum ether and ethyl acetate to obtain the target compound with a yield of 55%.R )-Methyl lactate (1.5 mmol, 1.5 equiv.) and triethylamine (1.5 mmol, 1.5 equiv.) were added, and finally a reflux condenser was added. The mixture was stirred at 120 o °C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure to obtain the crude product, and then the target compound was obtained by recrystallization from petroleum ether and ethyl acetate, with a yield of trace.

[0025] Example 8: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, then 1,4-dioxane (5.0 mL) was added and stirred evenly. Subsequently, ( R )-Methyl lactate (1.5 mmol, 1.5 equiv.) and sodium carbonate (1.5 mmol, 1.5 equiv.) were added, and finally a reflux condenser was added. The mixture was stirred at 120 o °C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure to obtain the crude product, and then the target compound was obtained by recrystallization from petroleum ether and ethyl acetate, with a yield of trace.

[0026] Example 9: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, then 1,4-dioxane (5.0 mL) was added and stirred evenly. Subsequently, ( R )-Methyl lactate (1.5 mmol, 1.5 equiv.) and sodium hydroxide (1.5 mmol, 1.5 equiv.) were added, and finally a reflux condenser was added. The mixture was stirred at 120 o °C for 12 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure to obtain the crude product, and then the target compound was obtained by recrystallization from petroleum ether and ethyl acetate, with a yield of trace.

[0027] Example 10: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, then 1,4-dioxane (5.0 mL) was added and stirred evenly. Subsequently, ( R )-Methyl lactate (1.5 mmol, 1.5 equiv.) and sodium methoxide (1.5 mmol, 1.5 equiv.) were added, and finally a reflux condenser was added. The mixture was stirred at 120 oStir the reaction at 120 °C for 12 h. After the reaction is completed, cool it to room temperature, add water and dichloromethane for extraction, and collect the organic phase. Dry and filter over anhydrous sodium sulfate, remove the solvent under reduced pressure to obtain the crude product, and then recrystallize with petroleum ether and ethyl acetate to obtain the target compound with a yield of 82%.

[0028] Example 11: Add 3,5-dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) to a 150 mL reaction flask, then add 1,4-dioxane (5.0 mL) and stir evenly. Subsequently, add ( R -methyl lactate (1.5 mmol, 1.5 equiv.) and potassium tert-butoxide (1.5 mmol, 1.5 equiv.), and finally add a reflux condenser and stir the reaction at 120 o °C for 12 h. After the reaction is completed, cool it to room temperature, add water and dichloromethane for extraction, and collect the organic phase. Dry and filter over anhydrous sodium sulfate, remove the solvent under reduced pressure to obtain the crude product, and then recrystallize with petroleum ether and ethyl acetate to obtain the target compound with a yield of 74%.

[0029] Example 12: Add 3,5-dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) to a 150 mL reaction flask, then add 1,4-dioxane (5.0 mL) and stir evenly. Subsequently, add ( R -methyl lactate (1.5 mmol, 1.5 equiv.) and sodium hydride (1.5 mmol, 1.5 equiv.), and finally add a reflux condenser and stir the reaction at 120 o °C for 12 h. After the reaction is completed, cool it to room temperature, add water and dichloromethane for extraction, and collect the organic phase. Dry and filter over anhydrous sodium sulfate, remove the solvent under reduced pressure to obtain the crude product, and then recrystallize with petroleum ether and ethyl acetate to obtain the target compound with a yield of 47%.

[0030] Example 13: Add 3,5-dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) to a 150 mL reaction flask, then add tetrahydrofuran (5.0 mL) and stir evenly. Subsequently, add ( R -methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.), and finally add a reflux condenser and stir the reaction at 60 o °C for 12 h. After the reaction is completed, cool it to room temperature, add water and dichloromethane for extraction, and collect the organic phase. Dry and filter over anhydrous sodium sulfate, remove the solvent under reduced pressure to obtain the crude product, and then recrystallize with petroleum ether and ethyl acetate to obtain the target compound with a yield of 86%.

[0031] Example 14: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, then tetrahydrofuran (5.0 mL) was added and stirred evenly. Subsequently, ( R -methyl lactate (1.5 mmol, 1.5 equiv.) and sodium tert-butoxide (1.5 mmol, 1.5 equiv.) were added. Finally, a condenser reflux tube was added and the mixture was stirred at 80 o °C for 6 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized from petroleum ether and ethyl acetate to obtain the target compound with a yield of 90% and ee: 89%.

[0032] Example 15: 3,5-Dichloro-2,6-difluoropyridin-4-amine (1.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, then tetrahydrofuran (5.0 mL) was added and stirred evenly. Subsequently, ( R -methyl lactate (1.0 mmol, 1.0 equiv.) and sodium tert-butoxide (1.0 mmol, 1.0 equiv.) were added. Finally, a condenser reflux tube was added and the mixture was stirred at 60 o °C for 6 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized from petroleum ether and ethyl acetate to obtain the target compound with a yield of 87%.

[0033] Example 16: 3,5-Dichloro-2,6-difluoropyridin-4-amine (10.0 mmol, 1.0 equiv.) was added to a 150 mL reaction flask, then tetrahydrofuran (50.0 mL) was added and stirred evenly. Subsequently, ( R -methyl lactate (15.0 mmol, 1.5 equiv.) and sodium tert-butoxide (22.5 mmol, 2.3 equiv.) were added. Finally, a condenser reflux tube was added and the mixture was stirred at 80 o °C for 6 h. After the reaction was completed, it was cooled to room temperature, water and dichloromethane were added for extraction, and the organic phase was collected. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Subsequently, it was recrystallized from petroleum ether and ethyl acetate to obtain the target compound with a yield of 98% and ee: 91%. 1 1H NMR (600 MHz, CDCl3) δ5.28 - 5.24 (m, 1H), 5.16 (s, 2H), 3.74 (s, 3H), 1.62 (d, 6.0 Hz, 3H). Chiral test conditions for the intermediate of flumiclorac - pentyl: Column: CHIRALCEL OJ - H (4.6 mm * 250 mm, 5 µm); Mobile phase: n - hexane: isopropanol: trifluoroacetic acid (700:300:1); Flow rate: 0.8 mL / min; Wavelength: 210 nm; Injection volume: 10 μL; Column temperature: 35 °C; Collection time: 15 min; Retention time: R - methyl ester 9.02 min, S - methyl ester 11.9 min.

[0034] From the above examples, it can be seen that the yield of the synthesis method of this application can reach 98%, and the ee value is 91%.

[0035] The above - mentioned are only the preferred embodiments of the present invention, and do not impose any formal limitations on the present invention. Any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A preparation method of a flumiclorac - pentyl intermediate, characterized in that, It includes the following steps: Using 3,5-dichloro-2,6-difluoro-pyridin-4-amine and methyl ( R )-lactate as raw materials, the intermediate of flumiclorac-pentyl is generated through a nucleophilic substitution reaction; The structural formula of the flumiclorac - pentyl intermediate is as follows: 。 2. The preparation method of a flumiclorac - pentyl intermediate according to claim 1, characterized in that, The synthesis route is as follows: 。 3. The preparation method of a flumiclorac - pentyl intermediate according to claim 2, characterized in that, In the synthesis reaction, the base is any one or a combination of sodium bicarbonate, potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, N , N -diisopropylethylamine, 2,6-dimethylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride.

4. The preparation method of a flumiclorac pentyl intermediate as claimed in claim 2, wherein, In the synthesis reaction, the solvent is dimethyl sulfoxide, N , N N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, ethylbenzene, or any combination thereof.

5. The preparation method of a flumiclorac - pentyl intermediate as claimed in claim 2, characterized in that, In the synthesis reaction, the reaction temperature is 0 - 120 °C.

6. The preparation method of a flumiclorac - pentyl intermediate according to claim 2, characterized in that, In the synthesis reaction, the reaction time is 0.5 - 24 h.

7. The preparation method of a flumiclorac - pentyl intermediate according to claim 2, characterized in that, The molar ratio of 3,5-dichloro-2,6-difluoro-pyridin-4-amine shown by the general formula to methyl ( R -lactate is 1 to 3; ( R The molar ratio of methyl -lactate to the base is 1 to 3, and the solvent amount is 0.01 - 1 M (relative to 3,5-dichloro-2,6-difluoro-pyridin-4-amine).

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