Preparation method of stable isotope labeled fluridone internal standard reagent
The preparation of stable isotope-labeled fluoridone internal standard reagent through a two-step Suzuki coupling reaction, which solved the problems of low detection sensitivity and detection limit in the prior art, and achieved high purity and high abundance fluoridone internal standard reagent in the fluoridone The preparation of standard reagents meets the needs of food safety testing.
Patent Information
- Application Number
- CN202411287510.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-13
- Publication Date
- 2024-12-13
AI Technical Summary
The existing technology cannot effectively prepare the internal standard reagent of stable isotope labeled flunoxalone, resulting in low detection sensitivity and high detection limit in food safety testing, and lack of corresponding supply of stable isotope labeled compounds, which cannot meet the domestic and foreign pesticide residue detection. need.
Using two-step Suzuki coupling reaction, simple and easy-to-get intermediates such as 3,5-dibromonyl-1-methylpyridine-4(1H)-one and 3-trifluoromethylbenzene boric acid, the reaction was carried out under mild conditions. , a stable isotope-labeled fluoridone internal standard reagent with chemical purity above 99% and isotope abundance above 98%.
It has achieved efficient preparation of the internal standard reagent of stable isotope labeled with fluoridone for food safety detection, reduced product costs, improved detection sensitivity, and met the application needs of food safety supervision and supervision.
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Figure CN119118915A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing a stable isotope labeled flupyralidone internal standard reagent for food safety (pesticide residue) detection, and belongs to the field of research and development of standard substances for food safety (pesticide residue detection). Background Art
[0002] Fluridone is a pyridone herbicide that can be used to control most weeds in water or on the water surface. It can also be used as a pre-emergence selective herbicide to control annual narrow-leaved and broad-leaved weeds and some perennial weeds in cotton. Fluridone has been widely used abroad, and a variety of formulations have been approved in China. Due to its unreasonable use, it is easy to remain on crops, thus affecting people's health safety. Based on safety considerations, the U.S. Environmental Protection Agency issued Regulation No. 2023-00949 on January 20, 2023, conducting a risk assessment on its toxicity, dietary exposure, and effects on infants and young children, and revised its residue limit in some products to 0.1-0.15 mg / kg. Japan also stipulates that its residue limit in animal-derived foods is 0.01-0.05 mg / kg. my country also stipulates in the "GB 2763.1-2022 National Food Safety Standard Maximum Residue Limits of 112 Pesticides including 2,4-D Butyrate Sodium Salt in Food" that the maximum residue limit of fluazifop-methyl in cotton seeds is 0.02 mg / kg. At the same time, my country's standards for detecting this substance include "GB 23200.11-2016 National Food Safety Standard Determination of 413 Pesticides and Related Chemical Residues in Mulberry Branches, Honeysuckle, Lycium Barbarum and Lotus Leaves by Liquid Chromatography-Mass Spectrometry", "GB 23200.12-2016 National Food Safety Standard Determination of 440 Pesticides and Related Chemical Residues in Edible Fungi by Liquid Chromatography-Mass Spectrometry", "GB 23200.13-2016 National Food Safety Standard Determination of 448 Pesticides and Related Chemical Residues in Tea by Liquid Chromatography-Mass Spectrometry", "GB 23200.14-2016 National Food Safety Standard Determination of 512 Pesticides and Related Chemical Residues in Fruit and Vegetable Juice and Fruit Wine by Liquid Chromatography-Mass Spectrometry", and "GB 23200.50-2016 National Food Safety Standard Determination of Pyridine Pesticide Residues in Food by Liquid Chromatography-Mass Spectrometry / Mass Spectrometry". Since there is no corresponding stable isotope labeled internal standard compound available, only the external standard method can be used for quantitative detection. Stable isotope dilution mass spectrometry is the internationally recognized "gold standard" for trace detection. Using the stable isotope labeled compound corresponding to the compound as the internal standard and using the internal standard method for quantitative detection can significantly improve the sensitivity of the compound detection and reduce the detection limit of the compound. At present, there is no literature report on the preparation of stable isotope labeled flupyridam. Therefore, the development of stable isotope labeled flupyridam internal standard reagents is of great significance for the innovative development of my country's food safety (pesticide residue) detection related fields and filling the gaps at home and abroad.
[0003] At present, the synthesis routes of this naturally abundant compound in the prior art mainly include the following: Route 1: "Synthesis of β-aminostyrens" (US4264775) uses 3-trifluoromethylaniline as a raw material, and prepares flupyralidone through diazotization, alkylation, condensation, amidation, and cyclization reactions. The route is shown in the following reaction formula:
[0004] Route 2: "Method of controlling aquatic weeds and algae" (US4235619) uses 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone with sodium methoxide and methyl formate to generate a sodium dienolate intermediate, and finally the sodium dienolate intermediate reacts with methylamine hydrochloride to generate flupyralidone. The route is shown in the following reaction formula:
[0005] Route 3: "A method for preparing pyridone compounds and intermediates thereof" (CN115894352 A) is to react 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone with N,N-dimethylformamide diacetal, and then react with methylamine aqueous solution to obtain flupyralidone. The route is shown in the following reaction formula:
[0006] The phenylacetyl chloride in the above route 1 is not an isotope-labeled commercial reagent and is not easy to obtain; the intermediates used in routes 2 and 3 are both 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone, the synthesis steps of the intermediate are long and it is not easy to obtain a stable isotope-labeled compound of the structure, so the above routes are not suitable for synthesizing stable isotope-labeled flupyralidone internal standard reagents.
[0007] To date, there are no reports in the literature on the structure and synthetic process route of stable isotope-labeled flupyralidone internal standard reagent.
[0008] Therefore, there is an urgent need to develop a method for preparing a stable isotope-labeled flupyralidone internal standard reagent with low stable isotope raw material price, short reaction route, mild reaction conditions, high total yield of the final product, easy separation and purification, and undiluted isotope abundance, so as to meet the growing application demand of this compound in domestic food safety supervision and regulation. Summary of the invention
[0009] The object of the present invention is to provide a method for preparing a stable isotope-labeled flupyridone internal standard reagent suitable for food safety detection. The intermediates and stable isotope raw materials required for the preparation method are simple, easy to obtain and inexpensive, the reaction conditions are mild, the reaction steps only require two steps of Suzuki coupling, and the atomic economy of the stable isotope-labeled raw materials is high. The chemical purity of the target product stable isotope-labeled flupyridone can reach more than 99%, the isotope abundance can reach more than 98%, and the final product yield is high, the isotope abundance is not diluted, and the product cost is effectively reduced.
[0010] The purpose of the present invention can be achieved by the following technical solutions: A method for preparing stable isotope-labeled flupyridone for food safety (pesticide residue detection), wherein the chemical structure of the stable isotope-labeled flupyridone is shown in the formula (stable isotope-labeled flupyridone):
[0011] Where X is H or D, * is 12 C or 13 C, and X and * are not H and 12 C, characterized in that the general route of its preparation steps is:
[0012] The preparation steps are as follows: (1) In the presence of a catalyst, a ligand, a base and a solvent, add 3,5-dibromo-1-methylpyridine-4(1 H )-ketone (I) and one of 3-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid ester and 3-trifluoromethylcatecholboronic acid ester (II) are reacted at 30°C to 150°C for 6 to 48 hours; after TLC tracking, the reaction mixture is quenched with water, filtered, and the filtrate is extracted with an organic solvent. The organic phases are combined, washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, dried with a desiccant, and the solvent is removed by distillation under reduced pressure. The residue is subjected to column chromatography to obtain 1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H -pyridin-4-one (III); The reaction of this step is as follows:
[0013] (2) In the presence of a catalyst, a ligand, a base, and a solvent, add one of the stable isotope-labeled phenylboronic acid, the stable isotope-labeled phenylboronic acid pinacol ester, and the stable isotope-labeled phenylboronic acid catechol ester (IV), and then add 1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H-pyridin-4-one (III), react at 30°C to 150°C for 6 to 48 hours; after the reaction of the raw materials is completed by TLC tracking, the reaction mixture is quenched with water, filtered, the filtrate is extracted with an organic solvent, the organic phases are combined, washed with water, washed with a saturated sodium bicarbonate solution, washed with a saturated sodium chloride solution, dried with a desiccant, and the solvent is removed by distillation under reduced pressure. The residue is subjected to column chromatography to obtain stable isotope-labeled flupyradone.
[0014] The reaction of this step is as follows:
[0015] In the step (1), the compound (II) is one of 3-trifluoromethylboric acid, 3-trifluoromethylboric acid pinacol ester, and 3-trifluoromethylboric acid phthalate; the catalyst is one or more of tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone palladium, palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinodifluorocene)palladium dichloride, bis(tricyclohexylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium chloroform adduct, and bis(triphenylphosphine)palladium dichloride; the ligand is 2-dicyclohexylphosphine-2'-methylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (S-Phos), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, n-butyldi(1-gold) any one or more of the following: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, bis(2-diphenylphosphophenyl)ether, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl; the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, cesium fluoride, etc.; the solvent is one or more of tetrahydrofuran, 1,4-dioxane, acetone, toluene, xylene, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, n-propanol, benzene, water; the reaction temperature is 30°C to 150°C; the reaction time is 6 to 48 hours.
[0016] Preferably, the molar ratio of compound (II) to compound (I) in step (1) is (1:1) to (1:1.5); Preferably, the catalyst in step (1) is one of tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinoferrocene)palladium dichloride, and bis(triphenylphosphine)palladium dichloride; the molar ratio of the compound (I) to the catalyst is (1:0.005) to (1:0.1); Preferably, the ligand in step (1) is any one of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl; the molar ratio of the compound (I) to the ligand is (1:0.01) to (1:0.15); Preferably, the base in step (1) is one or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate; the molar ratio of compound (I) to the base is (1:1) to (1:5); Preferably, the organic solvent in step (1) is one or more of ethanol, 1,4-dioxane, toluene and water; Preferably, the reaction temperature in step (1) is 50°C to 120°C; Preferably, the reaction time in step (1) is 12 to 24 hours.
[0017] In the step (2), the catalyst is one or more of tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone palladium, palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinoferrocene)palladium dichloride, bis(tricyclohexylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium chloroform adduct, and bis(triphenylphosphine)palladium dichloride; the ligand is 2-dicyclohexylphosphine-2'-methylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (S-Phos), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, n-butyldi(1-adamantyl)phosphine, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, Any one or more of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bis(2-diphenylphosphinophenyl)ether, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl; the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, cesium fluoride, etc.; the solvent is one or more of tetrahydrofuran, 1,4-dioxane, acetone, toluene, xylene, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, n-propanol, benzene, water; the reaction temperature is 30°C to 150°C; the reaction time is 6 to 48 hours; Preferably, in step (2), the molar ratio of compound (IV) to compound (III) is (1:1) to (1:1.5); Preferably, the catalyst in step (2) is one of tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinoferrocene)palladium dichloride, and bis(triphenylphosphine)palladium dichloride; the molar ratio of the compound (IV) to the catalyst is (1:0.005) to (1:0.1); Preferably, the ligand in step (2) is any one of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl; the molar ratio of the compound (IV) to the ligand is (1:0.01) to (1:0.15); Preferably, the base in step (2) is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or sodium tert-butoxide, potassium tert-butoxide; the molar ratio of the compound (IV) to the base is (1:1) to (1:5); Preferably, the organic solvent in step (2) is one or more of ethanol, 2-methyltetrahydrofuran, toluene, and N,N-dimethylformamide; Preferably, the reaction temperature in step (2) is 50°C to 120°C; Preferably, the reaction time in step (2) is 12 to 24 hours.
[0018] Compared with the prior art, the beneficial effects of the present invention are: the raw materials used in the preparation method of the stable isotope-labeled flupyridone internal standard reagent for food safety detection of the present invention are simple, easy to obtain and low-cost, the synthesis steps are short, the reaction conditions are mild, and the final product has the advantages of few side reactions, easy separation and purification, high chemical purity, high total yield, and no dilution of isotopic abundance. The preparation route and method of the stable isotope-labeled flupyridone internal standard reagent have not been reported in the literature. The chemical purity of the stable isotope-labeled flupyridone prepared by the method is greater than 99%, and the isotopic abundance is greater than 98%. The stable isotope-labeled flupyridone internal standard reagent for food safety detection prepared by this preparation method is of great significance to the development of relevant food safety supervision and detection technologies in my country. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 :1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H -pyridin-4-one 1 H NMR diagram Figure 2 :1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H LC-MS chart of -pyridin-4-one Figure 3 : Flupyridamole-D5 (Phenyl-D5) 1 H NMR diagram Figure 4 :LC-MS chart of flupyralidone-D5 (phenyl-D5) Figure 5 :HPLC chart of flupyralidone-D5 (phenyl-D5) DETAILED DESCRIPTION
[0020] The present invention will be further described below in conjunction with the embodiments and the accompanying drawings, but this does not limit the scope of the present invention in any way.
[0021] Example 1: 1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H - Preparation of pyridin-4-one
[0022] In a 50 mL three-necked flask, add 3-trifluoromethylboric acid (380 mg, 2 mmol), 3,5-dibromo-1-methylpyridine-4(1 H )-ketone (588mg, 2.2mmol), potassium phosphate (1.06g, 5mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (17mg, 0.04mmol), palladium acetate (45mg, 0.2mmol), 1,4-dioxane (15mL); react at 80℃ for 16 hours; TLC tracking reaction raw materials after the reaction is complete, the reaction solution is cooled to room temperature, filtered and evaporated to remove the solvent under reduced pressure, 30mL of water is added, extracted with ethyl acetate (3×30mL), the organic phases are combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure. The residue is subjected to column chromatography to obtain 1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H -pyridin-4-one (418 mg, yield 63%).
[0023] Example 2: 1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H - Preparation of pyridin-4-one
[0024] In a 50 mL three-necked flask, add 3-trifluoromethylboronic acid pinacol ester (544 mg, 2 mmol), 3,5-dibromo-1-methylpyridine-4(1 H )-ketone (640mg, 2.4mmol), cesium phosphate (1.3g, 5mmol), tetrakistriphenylphosphine palladium (138mg, 0.12mmol), toluene (15mL), water (5mL); react at 110℃ for 12 hours; TLC tracking reaction raw materials after the reaction is complete, the reaction solution is cooled to room temperature, filtered and evaporated to remove the solvent under reduced pressure, 30mL of water is added, extracted with ethyl acetate (3×30mL), the organic phases are combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, dried with anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure. The residue is subjected to column chromatography to obtain 1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H-pyridin-4-one (478 mg, yield 72%). 1 H NMR (DMSO-D6, 600 MHz): δ8.33 (d, 1H), 8.14 (d, 1H), 8.09 (m, 1H), 7.97-7.95 (m, 1H), 7.68-7.62 (m, 2H), 3.76 (s, 3H), see Appendix Figure 1 ;LC-MS (ESI+) 332, 334[M+H] + , see attached Figure 2 .
[0025] Example 3: Preparation of Stable Isotope Labeled Flupyridamole (Phenyl-D5)
[0026] In a 50 mL three-necked flask, add phenylboronic acid-D5 (254 mg, 2 mmol), 3,5-dibromo-1-methylpyridine-4 (1 H )-ketone (730 mg, 2.2 mmol), potassium phosphate (1.27 g, 6 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.15 mmol), palladium acetate (22 mg, 0.1 mmol), N,N-dimethylformamide (15 mL); react at 100 ° C for 10 hours; TLC tracking reaction raw materials after the reaction is complete, the reaction solution is cooled to room temperature, filtered and evaporated to remove the solvent under reduced pressure, 20 mL of water is added, extracted with dichloromethane (2×30 mL), the organic phases are combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, added with anhydrous sodium sulfate to dry, and the solvent is evaporated to remove under reduced pressure. The residue is subjected to column chromatography to obtain stable isotope labeled flupyridam (phenyl-D5) (555 mg, yield 83%). 1 H NMR (DMSO-D6, 600 MHz): δ8.16 (s, 1H), 8.09 (d, 1H), 8.00-7.98 (m, 1H), 7.95 (d, 1H), 7.67-7.62 (m, 2H), 3.80 (s, 3H), see Appendix Figure 3 ; LC-MS (ESI+) 335 [M+H] + , see attached Figure 4 HPLC measured chemical purity of 99.02%, see attached Figure 5 . Isotopic abundance = 99.9%, see Table 1.
[0027] Table 1 Isotopic abundance of flupyralidone-D5 (phenyl-D5) Relative strength (%) <![CDATA[D0]]> 0 <![CDATA[D1]]> 0 <![CDATA[D2]]> 0 <![CDATA[D3]]> 0 <![CDATA[D4]]> 0.5 <![CDATA[D5]]> 99.5 %D 99.9 The quality standards meet the quality requirements for stable isotope labeled internal standard reagents required for liquid chromatography tandem mass spectrometry for food safety (pesticide residues) testing.
[0028] The above is only a preferred embodiment of the present invention, but the present invention should not be limited to the contents disclosed in the embodiment. Therefore, any equivalent or modification completed without departing from the spirit disclosed in the present invention shall fall within the scope of protection of the present invention.
Claims
1. A method for preparing stable isotope-labeled flupyridone for food safety (pesticide residue) detection, wherein the chemical structure of the stable isotope-labeled flupyridone is shown in the formula (stable isotope-labeled flupyridone): Where X is H or D, * is 12 C or 13 C, and X and * are not H and 12 C, characterized in that The general route of preparation steps is: ； The preparation steps are as follows: (1) In the presence of a catalyst, a ligand, a base and a solvent, add 3,5-dibromo-1-methylpyridine-4(1 H )-ketone (I) and one of 3-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid ester and 3-trifluoromethylcatecholboronic acid ester (II) are reacted at 30°C to 150°C for 6 to 48 hours; after TLC tracking, the reaction mixture is quenched with water, filtered, and the filtrate is extracted with an organic solvent. The organic phases are combined, washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, dried with a desiccant, and the solvent is removed by distillation under reduced pressure. The residue is subjected to column chromatography to obtain 1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H -pyridin-4-one (III); The reaction of this step is as follows: (2) In the presence of a catalyst, a ligand, a base, and a solvent, add one of the stable isotope-labeled phenylboronic acid, the stable isotope-labeled phenylboronic acid pinacol ester, and the stable isotope-labeled phenylboronic acid catechol ester (IV), and then add 1-methyl-3-bromo-5-(3-trifluoromethylphenyl)-1 H -pyridin-4-one (III), react at 30°C to 150°C for 6 to 48 hours; after the reaction of the raw materials is completed by TLC tracking, the reaction mixture is quenched with water, filtered, the filtrate is extracted with an organic solvent, the organic phases are combined, washed with water, saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with a desiccant, and the solvent is removed by distillation under reduced pressure. The residue is subjected to column chromatography to obtain stable isotope-labeled flupyridamyl; The reaction of this step is as follows: .
2. The method for preparing a stable isotope labeled fluopyraclostrobin internal standard reagent according to claim 1, characterized in that: In the step (1), the compound (II) is one of 3-trifluoromethylboric acid, 3-trifluoromethylboric acid pinacol ester, and 3-trifluoromethylboric acid phthalate; the catalyst is one or more of tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone palladium, palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinodifluorocene)palladium dichloride, bis(tricyclohexylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium chloroform adduct, and bis(triphenylphosphine)palladium dichloride; the ligand is 2-dicyclohexylphosphine-2'-methylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (S-Phos), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, n-butyldi(1-gold) any one or more of the following: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthene, bis(2-diphenylphosphophenyl)ether, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl; the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, cesium fluoride, etc.; the solvent is one or more of tetrahydrofuran, 1,4-dioxane, acetone, toluene, xylene, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, n-propanol, benzene, water; the reaction temperature is 30°C to 150°C; the reaction time is 6 to 48 hours; Preferably, the molar ratio of compound (II) to compound (I) in step (1) is (1:1) to (1:1.5); Preferably, the catalyst in step (1) is one of tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinoferrocene)palladium dichloride, and bis(triphenylphosphine)palladium dichloride; the molar ratio of the compound (I) to the catalyst is (1:0.005) to (1:0.1); Preferably, the ligand in step (1) is any one of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl; the molar ratio of the compound (I) to the ligand is (1:0.01) to (1:0.15); Preferably, the base in step (1) is one or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate; the molar ratio of compound (I) to the base is (1:1) to (1:5); Preferably, the organic solvent in step (1) is one or more of ethanol, 1,4-dioxane, toluene and water; Preferably, the reaction temperature in step (1) is 50°C to 120°C; Preferably, the reaction time in step (1) is 12 to 24 hours.
3. The method for preparing a stable isotope labeled fluopicolide internal standard reagent according to claim 1, characterized in that: In the step (2), the catalyst is one or more of tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone palladium, palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinoferrocene)palladium dichloride, bis(tricyclohexylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium chloroform adduct, and bis(triphenylphosphine)palladium dichloride; the ligand is 2-dicyclohexylphosphine-2'-methylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (S-Phos), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, n-butyldi(1-adamantyl)phosphine, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, Any one or more of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, bis(2-diphenylphosphinophenyl)ether, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl; the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, potassium fluoride, cesium fluoride, etc.; the solvent is one or more of tetrahydrofuran, 1,4-dioxane, acetone, toluene, xylene, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, n-propanol, benzene, water; the reaction temperature is 30°C to 150°C; the reaction time is 6 to 48 hours; Preferably, in step (2), the molar ratio of compound (IV) to compound (III) is (1:1) to (1:1.5); Preferably, the catalyst in step (2) is one of tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinoferrocene)palladium dichloride, and bis(triphenylphosphine)palladium dichloride; the molar ratio of the compound (IV) to the catalyst is (1:0.005) to (1:0.1); Preferably, the ligand in step (2) is any one of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl; the molar ratio of the compound (IV) to the ligand is (1:0.01) to (1:0.15); Preferably, the base in step (2) is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or sodium tert-butoxide, potassium tert-butoxide; the molar ratio of the compound (IV) to the base is (1:1) to (1:5); Preferably, the organic solvent in step (2) is one or more of ethanol, 2-methyltetrahydrofuran, toluene, and N,N-dimethylformamide; Preferably, the reaction temperature in step (2) is 50°C to 120°C; Preferably, the reaction time in step (2) is 12 to 24 hours.