A kind of preparation method of clofopyralid

Abstract

The invention provides a method for preparing clofopyralid, which does not require the use of expensive palladium catalysts and toxic and environmentally unfriendly phosphine ligands. The invention adopts a new copper catalytic system, in which a copper catalyst, a N-containing ligand and a phase transfer catalyst are used together as the catalyst system. Clofopyralid can be obtained with high yield and high purity, and can be scaled up to kilogram level, which is more suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of small molecules of organic pesticides, and in particular to a method for preparing clofopyralid. Background Art

[0002] Fluopyridine-methyl (HRF) is a picolinate aromatic ester herbicide developed by Dow AgroSciences. It binds tightly to the plant target AFB5, inducing an increase in related activities in sensitive plant cells, leading to abnormal plant growth, such as tissue swelling, stem bending, etc., and ultimately leading to plant death. At present, the main methods for preparing HRF are: Patent CN201280014371.4 uses expensive bistriphenylphosphine palladium dichloride as a catalyst in the preparation of HRF, and Patent CN201780042463.6 also uses expensive palladium acetate as a catalyst, and adds toxic and environmentally polluting triphenylphosphine as a ligand, with a yield of 67.9%-81.4%, and Patent WO2021 / 188654A1 also uses expensive palladium acetate as a catalyst, and adds toxic and environmentally polluting triphenylphosphine as a ligand, with a yield of 73-89%. It can be seen that the prior art has the problem of needing to add expensive precious metal catalysts, toxic and environmentally polluting phosphine ligands, and low yield and purity. Therefore, it is necessary to provide a method for preparing HRF with low cost, high yield and no need to use toxic and environmentally polluting ligands. Summary of the invention

[0003] The object of the present invention is to provide a method for preparing cloflupyridine-methyl to solve the technical problems existing in the prior art of using noble metal catalysts, toxic and environmentally polluting phosphine ligands, and low yield and low purity.

[0004] In order to solve the above technical problems, the present invention provides a preparation method of chlorpyrifos, which is characterized by the specific synthesis process: using 4-amino-6-bromo-3-chloro-5-fluoropicolinic acid benzyl ester (compound A) and 4-chloro-2-fluoro-3-methoxyphenylboronic acid (compound B) as reaction raw materials, under nitrogen protection, using a copper catalyst, a N-containing ligand and a phase transfer catalyst as a catalyst system, in the presence of a base and a solvent, reacting at 110-150° C. for a certain time to obtain the target compound 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid benzyl ester (compound C), and the reaction route in the synthesis method is:

[0005]

[0006] Further preferably, the preparation method of cloflupyridine-methyl is characterized in that the specific operating steps are: adding compound A, compound B, copper catalyst, N-containing ligand, phase transfer catalyst, base and solvent to a round-bottom flask with a condenser, sealing the reaction device, and replacing it with nitrogen, raising the reaction temperature to 110-150°C, reacting for 18-36 hours under stirring, and after the reaction is completed by TLC monitoring, cooling to room temperature, filtering, adding dichloromethane and water to extract, separating the organic phase, and drying with anhydrous sodium sulfate, filtering, and spin-drying to finally obtain a crude product of the target product compound C, dissolving the above crude product in an organic solvent, cooling and crystallizing, filtering, and drying to obtain a pure product of compound C.

[0007] Further preferably, the copper catalyst is selected from: a combination of one or more of CuI, CuBr or CuCl;

[0008] More preferably, the N-containing ligand is selected from: one or a combination of sparteine, triethylenediamine, (1R, 2R)-(-)-1,2-cyclohexanediamine, (1S, 2S)-(-)-1,2-cyclohexanediamine, and N,N'-dimethylethylenediamine;

[0009] More preferably, the phase transfer catalyst is selected from the group consisting of: benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, or a combination of one or more thereof;

[0010] More preferably, the base is selected from: a combination of one or more of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, KOH, and NaOH;

[0011] More preferably, the solvent is selected from: one or more combinations of 1,4-dioxane, DMSO, DMF, DMA, toluene, xylene, ethanol, butanol, and 1,2-dichloroethane;

[0012] Further preferably, the reaction temperature is 110-150°C, preferably 120°C;

[0013] Further preferably, the reaction time is 18-36 hours, preferably, 24-30 hours, more preferably, 24 hours;

[0014] More preferably, the organic solvent is selected from the group consisting of one or more of methanol, ethanol, ethyl acetate, butyl acetate, dichloromethane, acetone, toluene, petroleum ether, and n-hexane;

[0015] Further preferably, the molar feed ratio of compound A to compound B is: 1:1-5, preferably, 1:1-2, more preferably, 1:1.1-1.5;

[0016] Further preferably, the amount of the copper catalyst relative to compound A is: 5-30 mol%, preferably, 10-20 mol%, more preferably 10 mol%;

[0017] Further preferably, the amount of the N-containing ligand relative to compound A is: 10-50 mol%, preferably, 20-30 mol%, more preferably 20 mol%;

[0018] Further preferably, the amount of the phase transfer catalyst relative to compound A is: 10-100 mol%, preferably, 60-100 mol%, more preferably 100 mol%;

[0019] Further preferably, the molar ratio of the base to compound A is: 1:1-5, preferably, 1:2-3, more preferably 1:2;

[0020] Further preferably, the cooling crystallization temperature is 0-10°C, preferably 0-5°C, more preferably 0°C;

[0021] By adopting the above technical solution, the present invention has the following beneficial effects:

[0022] 1) The present invention adopts a new copper catalyst system, using a copper catalyst, a N-containing ligand and a phase transfer catalyst as a catalyst system, which is cheaper and more environmentally friendly, and does not require the use of expensive palladium catalysts, nor does it require the use of toxic and environmentally unfriendly phosphine ligands;

[0023] 2) The yield and purity of the present invention are high, the yield can reach up to 95% and the purity can reach 99%. Moreover, the yield of the present invention can be expanded to the kilogram level to obtain a 90% yield, which is more suitable for industrialization. DETAILED DESCRIPTION

[0024] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] The present invention is further explained below in conjunction with specific implementation modes.

[0026] Example 1

[0027]

[0028] Compound A (1 mmol, 0.359 g), compound B (1.1 mmol, 0.225 g), CuI (0.1 mmol, 0.02 g), spartine (0.2 mmol, 0.047 g), tetrabutylammonium bromide (1 mmol, 0.323 g) and cesium carbonate (2 mmol, 0.65 g) were weighed into a 50 mL round-bottom flask with a condenser, and 20 mL of 1,4-dioxane solution was added. The reaction apparatus was sealed and replaced with nitrogen. The reaction temperature was raised to 120 ° C and reacted under stirring. After 24 hours, the reaction was monitored by TLC, cooled to room temperature, filtered, extracted three times with dichloromethane (60 mL*3) and water (30 mL*3), separated the organic phase layer, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 0.416 g (yield: 94.7%) of the target product compound C. The crude product was dissolved in 5 mL of dichloromethane under heating, and 20 mL of n-hexane was added, cooled to 5°C, crystallized for 24 hours, filtered, and dried to obtain 0.37 g of pure white solid compound C, which was determined by HPLC to have a purity of 99.2%.

[0029] The NMR characterization data of the compound are as follows:

[0030] 1 H NMR (400MHz, CDCl3) δ=7.61-7.48(m,2H),7.48-7.22(m,5H),5.63(s,2H),4.95(s,2H),3.89(s,3H).

[0031] Example 2

[0032]

[0033] Compound A (1 mmol, 0.359 g), compound B (1.1 mmol, 0.225 g), CuI (0.1 mmol, 0.02 g), triethylenediamine (0.2 mmol, 0.023 g), tetrabutylammonium bromide (1 mmol, 0.323 g) and cesium carbonate (2 mmol, 0.65 g) were weighed into a 50 mL round-bottom flask with a condenser, and 20 mL of 1,4-dioxane solution was added. The reaction apparatus was sealed and replaced with nitrogen. The reaction temperature was raised to 120 ° C and stirred. The mixture was reacted for 24 h. After the reaction was completed under TLC monitoring, it was cooled to room temperature, filtered, extracted three times with dichloromethane (60 mL*3) and water (30 mL*3), separated the organic phase layer, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 0.351 g (yield: 80%) of a crude product of the target product, compound C. The crude product was dissolved in 5 mL of dichloromethane under heating, and 20 mL of n-hexane was added. The mixture was cooled to 5°C, crystallized for 24 hours, filtered, and dried to obtain 0.30 g of a pure white solid product of compound C. The purity was determined by HPLC to be 98.0%.

[0034] Example 3

[0035]

[0036] Compound A (1 mmol, 0.359 g), compound B (1.1 mmol, 0.225 g), CuI (0.1 mmol, 0.02 g), spartine (0.2 mmol, 0.047 g), tetrabutylammonium bromide (1 mmol, 0.323 g) and potassium carbonate (2 mmol, 0.276 g) were weighed into a 50 mL round-bottom flask with a condenser, and 20 mL of 1,4-dioxane solution was added. The reaction apparatus was sealed and replaced with nitrogen. The reaction temperature was raised to 120 ° C and stirred. The reaction was continued for 24 h. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature, filtered, and extracted three times with dichloromethane (60 mL*3) and water (30 mL*3). The organic phase was separated and dried over anhydrous sodium sulfate. The mixture was filtered and spin-dried to obtain 0.378 g (yield: 86%) of a crude product of the target product, compound C. The crude product was dissolved in 5 mL of dichloromethane under heating, and 20 mL of n-hexane was added. The mixture was cooled to 5°C, crystallized for 24 h, filtered, and dried to obtain 0.32 g of a pure white solid product of compound C. The purity was determined by HPLC to be 98.1%.

[0037] Example 4

[0038]

[0039] Compound A (1 mmol, 0.358 g), compound B (1.1 mmol, 0.225 g), CuBr (0.1 mmol, 0.014 g), spartine (0.2 mmol, 0.047 g), tetrabutylammonium bromide (1 mmol, 0.323 g) and cesium carbonate (2 mmol, 0.65 g) were weighed into a 50 mL round-bottom flask with a condenser, and 20 mL of 1,4-dioxane solution was added. The reaction apparatus was sealed and replaced with nitrogen. The reaction temperature was raised to 120 ° C and stirred. The mixture was reacted for 24 h. After the reaction was completed under TLC monitoring, it was cooled to room temperature, filtered, extracted three times with dichloromethane (60 mL*3) and water (30 mL*3), separated the organic phase layer, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 0.382 g (yield: 87%) of a crude product of the target product, compound C. The crude product was dissolved in 5 mL of dichloromethane under heating, and 20 mL of n-hexane was added. The mixture was cooled to 5°C, crystallized for 24 h, filtered, and dried to obtain 0.32 g of a pure white solid product of compound C. The purity was determined by HPLC to be 98.4%.

[0040] Example 5

[0041]

[0042] Compound A (1 mmol, 0.358 g), compound B (1.1 mmol, 0.225 g), CuI (0.1 mmol, 0.02 g), spartine (0.2 mmol, 0.047 g), tetrabutylammonium bromide (1 mmol, 0.323 g) and cesium carbonate (2 mmol, 0.65 g) were weighed into a 50 mL round-bottom flask with a condenser, and 20 mL of DMF solution was added. The reaction apparatus was sealed and replaced with nitrogen. The reaction temperature was raised to 120 ° C and the reaction was stirred for 2 hours. 4h, after the reaction was completed under TLC monitoring, it was cooled to room temperature, filtered, extracted three times with dichloromethane (60mL*3) and water (30mL*3), separated the organic phase layer, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 0.397g (yield: 90.5%) of the crude product of compound C. The crude product was dissolved in 5mL of dichloromethane under heating, and 20mL of n-hexane was added, cooled to 5°C, crystallized for 24 hours, filtered, and dried to obtain 0.35g of pure white solid compound C, which was determined by HPLC to be 99% pure.

[0043] Example 6

[0044]

[0045] Compound A (1 mmol, 0.358 g), compound B (1.1 mmol, 0.225 g), CuI (0.1 mmol, 0.02 g), spartine (0.2 mmol, 0.047 g) and cesium carbonate (2 mmol, 0.65 g) were weighed into a 50 mL round-bottom flask with a condenser, and 20 mL of 1,4-dioxane solution was added. The reaction apparatus was sealed and replaced with nitrogen. The reaction temperature was raised to 120 ° C and reacted for 24 h under stirring. The reaction was monitored by TLC. The reaction was controlled, cooled to room temperature, filtered, and extracted three times with dichloromethane (60 mL*3) and water (30 mL*3). The organic phase layer was separated and dried over anhydrous sodium sulfate. The mixture was filtered and spin-dried to obtain 0.184 g (yield: 42%) of a crude product of the target product, compound C. The crude product was dissolved in 5 mL of dichloromethane under heating, and 20 mL of n-hexane was added. The mixture was cooled to 5°C, crystallized for 24 hours, filtered, and dried to obtain 0.10 g of a pure white solid product of compound C, which had a purity of 81.2% as determined by HPLC.

[0046] Example 7

[0047]

[0048] Compound A (5 mol, 1.79 Kg), compound B (5.5 mol, 1.125 Kg), CuI (0.5 mol, 0.095 Kg), spartine (1 mol, 0.234 Kg), tetrabutylammonium bromide (5 mol, 1.62 Kg) and cesium carbonate (10 mol, 3.26 Kg) were weighed respectively in a 10 L reactor with a condenser, and 6 L of 1,4-dioxane solution was added. The reaction device was sealed and replaced with nitrogen. The reaction temperature was raised to 120 ° C. The reaction was stirred for 24 hours. After the reaction was monitored by TLC, it was cooled to room temperature, filtered, and dichloromethane (3 L * 3) and water (1.5 L * 3) were added to extract three times. The organic phase layer was separated and dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 1.97 Kg of a crude product of the target product Compound C (yield: 90%).

[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing clofopyralid, characterized in that: The specific operation process is as follows: Compound A and Compound B are used as reaction raw materials, under nitrogen protection, copper catalyst, N-containing ligand and phase transfer catalyst are used as catalyst system, in the presence of base and solvent, react at 120°C for a certain time to obtain target compound C; its synthesis route is as follows: ； The copper catalyst is selected from: CuI; the amount of the copper catalyst relative to compound A is 10-20 mol%; The N-containing ligand is selected from: sparteine; the amount of the N-containing ligand relative to compound A is 20-30 mol%; The phase transfer catalyst is selected from: tetrabutylammonium bromide; the amount of the phase transfer catalyst relative to compound A is 100 mol; The base is selected from: cesium carbonate; the molar ratio of the base to compound A is 1:2; The solvent is selected from: a combination of one or more of 1,4-dioxane and DMF; The molar feed ratio of the compound A to the compound B is 1:1.1-1.

5.

2. The preparation method according to claim 1, characterized in that: The method further comprises a purification operation, wherein the specific operation process is as follows: dissolving the crude compound C obtained in claim 1 in an organic solvent, cooling and crystallizing, filtering, and drying to obtain a pure compound C.

3. The method according to claim 2, characterized in that The organic solvent is selected from the group consisting of one or more of methanol, ethanol, ethyl acetate, butyl acetate, dichloromethane, acetone, toluene, petroleum ether, and n-hexane; and the cooling crystallization temperature is 0-5°C.

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