Dichlorobenzene cyclic carbon-14 labeled bixafen and preparation method thereof

Abstract

The invention provides dichlorophenylcarbon-14 labeled bixafen and a preparation method thereof, 3-(difluoromethyl)-N-[4-fluoro-2-(pinacol borate) phenyl]-1-methylpyrazole-4-formamide is synthesized as an intermediate, and the dichlorophenylcarbon-14 labeled bixafen is synthesized by utilizing the intermediate and a carbon-14 labeled raw material through a one-step method. The problems that in the prior art, the number of radioactive reaction steps is large, the number of generated radioactive waste is large, the total radiochemical yield of a target object is low, and operation safety is low are solved.

Description

Technical Field

[0001] The present invention relates to the field of radiochemical synthesis, and in particular to a dichlorophenyl ring carbon-14 labeled bixafen and a preparation method thereof. Background Art

[0002] Bixafen is a succinate dehydrogenase inhibitor fungicide with a pyrazoleamide structure. It inhibits complex II, a protein in the mitochondrial respiratory electron transport chain of pathogens, thereby blocking their energy metabolism and ultimately killing the pathogens. It combines preventive and therapeutic effects and is used as a foliar spray to control fungal diseases in a variety of crops, including cotton, vegetables, barley, corn, rice, soybeans, and wheat. It boasts a broad spectrum of efficacy and safety against non-target organisms, including humans, animals, the environment, and crops. In recent years, bixafen has become one of the fastest-growing and fastest-growing succinate dehydrogenase inhibitor fungicides in both domestic and international markets. It has quickly become a hot topic for development among major pesticide companies and has now become the fourth-largest product in this class.

[0003] To date, there are two main methods for the synthesis of bixafen: (1) Synthesis starting from the dichlorobenzene ring end: 3,4-dichlorobromobenzene (1) is subjected to Grignard reaction to prepare 3,4-dichlorophenylboronic acid (2), 3,4-dichlorophenylboronic acid (2) and 4-fluoro-2-bromoaniline (3) are subjected to Suzuki coupling to obtain 2-(3,4-dichlorophenyl)-4-fluoroaniline (4), 2-(3,4-dichlorophenyl)-4-fluoroaniline (4) is reacted with 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (5-1), 3-difluoromethyl-1-methylpyrazole-4-carbonyl chloride (5-2) or 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester (5-3) to obtain bifenthion. The specific synthetic route is as follows: Figure 1 In addition, 2-(3,4-dichlorophenyl)-4-fluoroaniline (4) can be prepared by using 3,4-dichloroaniline as the starting material, preparing the diazonium salt through diazotization reaction, and then condensing it with 4-fluoroaniline.

[0004] (2) Synthesis starting from the pyrazole ring end: 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (5-1), 3-difluoromethyl-1-methylpyrazole-4-carbonyl chloride (5-2) or 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid ethyl ester (5-3) are used as raw materials and reacted with 4-fluoro-2-bromoaniline (3) and 4-fluoro-2-iodoaniline (7) to obtain 3-(difluoromethyl)- N -(4-Fluoro-2-bromophenyl)-1-methylpyrazole-4-carboxamide (6) and 3-(difluoromethyl)- N-(4-fluoro-2-iodophenyl)-1-methylpyrazole-4-carboxamide (8), and then intermediate 6 or 8 is reacted with 3,4-dichlorophenylboronic acid (2) to obtain bixafenthionine by Suzuki reaction. The specific synthetic route is as follows: Figure 2 shown.

[0005] To ensure the safety of agricultural products and the environment after pesticide use, all registered pesticides for sale must undergo pesticide metabolism tests for pesticide safety evaluation. Radioisotope carbon-14-labeled bixafen is a necessary tracer in this pesticide metabolism test, among which dichlorophenyl ring carbon-14-labeled bixafen is one of the necessary tracers. However, the synthesis of dichlorophenyl ring carbon-14-labeled bixafen using the above two synthesis technology schemes for bixafen has the following shortcomings: ① The radioactive reaction route involving radioisotopes is long, which will inevitably lead to a decrease in the total radiochemical yield of the target product and consume more extremely expensive radioisotope raw materials, which will inevitably increase the cost; ② The research and development cycle involving radiation operations is long, and the operators are exposed to radiation sites for a long time, which increases the safety risks of personnel; ③ The multiple reaction steps involving radioisotopes will inevitably lead to an increase in the amount of radioactive waste generated during the labeling synthesis process, thereby increasing the cost of radioactive waste disposal.

[0006] Therefore, there is an urgent need for a synthesis method for radioactive isotope carbon-14 labeled bixafenthion that comprehensively solves the defects of the existing technology, such as high label preparation cost, high radioactive waste disposal cost, and low operational safety. Summary of the Invention

[0007] The present invention aims to provide a dichlorophenyl ring carbon-14 labeled bixafen and a preparation method thereof, thereby solving many problems in the prior art, such as the availability of radioactive synthetic raw materials, the total radiochemical yield of radioactive reactions, the cost of radioactive raw materials, operational safety, and the amount of radioactive waste generated during the research and development process, and providing a low-cost and highly safe preparation method for dichlorophenyl ring carbon-14 labeled bixafen.

[0008] In a first aspect, the present technical solution provides a method for preparing dichlorophenyl ring carbon-14 labeled bixafen, comprising the following steps: S1: Preparation of 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10): Under the protection of inert gas, 3-fluoro-6-aminophenylboronic acid pinacol ester (9) is reacted with any of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid (5-1), 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride (5-2) or 1-methyl-3-difluoromethylpyrazole-4-carboxylate (5-3) to obtain 3-(difluoromethyl)- N-[4-Fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10); or, Under the protection of inert gas, catalyst and base, N -(2-bromo-4-fluorophenyl)-3-difluoromethyl-1-methylpyrazole-4-carboxamide (11) reacts with a boron reagent in a solvent at a certain temperature to obtain 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10); S2: Preparation of dichlorophenyl ring carbon-14 labeled bixafen; Under the protection of inert gas, the presence of catalyst and base, 3-(difluoromethyl)- N -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) and carbon-14 labeled 3,4-dichlorobromo[phenyl-U- 14 C6]benzene (13-1), C14 labeled trifluoromethanesulfonic acid-3,4-dichloro[phenyl-U- 14 C6]phenyl ester (13-2) or C14 labeled 3,4-dichloroiodo[phenyl-U- 14 C6] benzene (13-3) is dissolved in a solvent and reacted at a certain temperature to obtain dichlorobenzene ring carbon-14 labeled bixafenthionine ( N -[2-(3,4-dichloro[phenyl-U- 14 C6]phenyl)-4-fluorophenyl]-3-(difluoromethyl)-1-methylpyrazole-4-carboxamide, A).

[0009] This scheme synthesized the intermediate 3-(difluoromethyl)- N -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10), and the use of radioisotope carbon-14 labeled raw materials (13-1, 13-2 or 13-2) and intermediates (10) in a one-step method to prepare dichlorophenyl ring carbon-14 labeled bixafen (A), which greatly shortens the reaction steps of radioisotope carbon-14 labeled raw materials, thereby improving the total radiochemical yield of the target dichlorophenyl ring carbon-14 labeled bixafen (A). This not only reduces the amount of carbon-14 labeled raw materials required in the radioactive synthesis process, but also reduces the amount of radioactive waste generated, thereby reducing the cost of purchasing radioactive raw materials and the cost of radioactive waste disposal; at the same time, it shortens the exposure time of radiation-related operators in radiation sites during the project, significantly improving safety.

[0010] Specifically, this scheme provides a synthesis of 3-(difluoromethyl)- N-[4-Fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) were synthesized by two methods, namely, 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) reacts with carbon-14 labeled raw materials in a one-step reaction to directly obtain dichlorophenyl ring carbon-14 labeled bixafenthionine.

[0011] In step S1, 3-(difluoromethyl)- N The first method of preparing 4-[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) is: Under the protection of inert gas, 3-fluoro-6-aminophenylboronic acid pinacol ester (9) is mixed with 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid (5-1), 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride (5-2) or 1-methyl-3-difluoromethylpyrazole-4-carboxylate (5-3) in an organic solvent and a condensing agent, a catalytic activator and a base are added to react to obtain 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10).

[0012] In some embodiments, the inert gas is dry argon and argon.

[0013] In some embodiments, 3-fluoro-6-aminophenylboronic acid pinacol ester (9) is mixed with any one of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid (5-1), 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride (5-2) or 1-methyl-3-difluoromethylpyrazole-4-carboxylate (5-3) in an organic solvent and a condensing agent, a catalytic activator and a base are added to react. The reaction mixture is extracted to obtain an extract, and the extract is washed, dried, filtered and chromatographed to obtain 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10).

[0014] The corresponding reaction equation is as follows: .

[0015] In some embodiments, the condensing agent is selected from one or any combination of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI); the catalytic active agent is an acylation catalyst or activator selected from 4-dimethylpyridine (DMAP), 4-pyrrolidinylpyridine (4-PPY), 1-hydroxybenzotriazole (HOBt), 2-(7-azobenzotriazole)- N , N , N′ , N′ -Tetramethyluronium hexafluorophosphate (HATU) or (ethyl 2-oximinocyanoacetate)- N , N - one or any combination of dimethyl-morpholinourea hexafluorophosphate (COMU).

[0016] Preferably, dicyclohexylcarbodiimide is selected as the condensing agent and 4-lutidine is selected as the catalytic activator; or, diisopropylcarbodiimide is selected as the condensing agent and 1-hydroxybenzotriazole is selected as the catalytic activator; or, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is selected as the condensing agent and 1-hydroxybenzotriazole is selected as the catalytic activator.

[0017] When 3-fluoro-6-aminophenylboronic acid pinacol ester (9) and 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid (5-1) are mixed in an organic solvent and a condensing agent, a catalyst activator and a base are added to react, the base is selected from triethylamine, diisopropylethylamine (DIPEA), N -methylmorpholine (NMM), N -methylpiperidine or any combination thereof; the organic solvent is selected from dichloromethane (DCM), N , N -dimethylformamide (DMF) or any combination thereof, and the reaction temperature is -5°C to 50°C.

[0018] In some embodiments, based on the amount of 3-fluoro-6-aminophenylboronic acid pinacol ester (9) being 1.0, the amount of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid is 1.0-3.0, the amount of the condensing agent is 1.0-3.0, the amount of the catalyst is 1.0-3.0, and the amount of the base is 2.0-4.0.

[0019] When 3-fluoro-6-aminophenylboronic acid pinacol ester (9) reacts with 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride (5-2), the base is selected from sodium carbonate, triethylamine, diisopropylethylamine (DIPEA), N -methylmorpholine (NMM), N-methylpiperidine, pyridine or any combination thereof; the organic solvent is selected from dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), cyclopentyl methyl ether (CPME), toluene or any combination thereof, and the reaction temperature is 20°C to 80°C.

[0020] In some embodiments, based on the amount of 3-fluoro-6-aminophenylboronic acid pinacol ester (9) being 1.0, the amount of 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride being 1.2-3.0, and the amount of base being 1.1-1.3.

[0021] When 3-fluoro-6-aminophenylboronic acid pinacol ester (9) reacts with 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid ethyl ester (5-3), the base is selected from one or any combination of sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), and potassium bis(trimethylsilyl)amide (KHMDS); the organic solvent is an ether solvent selected from one or any combination of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and cyclopentyl methyl ether (CPME), and the reaction temperature is 0°C~40°C.

[0022] In some embodiments, based on the amount of 3-fluoro-6-aminophenylboronic acid pinacol ester (9) being 1.0, the amount of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid ethyl ester being 1.3-1.7, and the amount of base being 1.5-2.5.

[0023] In step S1, 3-(difluoromethyl)- N The second method of preparing 4-[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) is: Under the protection of inert gas, catalyst and base, N -(2-bromo-4-fluorophenyl)-3-difluoromethyl-1-methylpyrazole-4-carboxamide (11) reacts with a boron reagent in a solvent at a certain temperature to obtain 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10).

[0024] In some embodiments, N -(2-bromo-4-fluorophenyl)-3-difluoromethyl-1-methylpyrazole-4-carboxamide (11) reacts with a boron reagent in a solvent at a certain temperature, and the reaction mixture is extracted to obtain an extract, and the extract is washed, dried, filtered and chromatographed to obtain 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10).

[0025] In some embodiments, the inert gas is dry argon and argon.

[0026] In some embodiments, the catalyst is selected from one or any combination of bis(triphenylphosphine)palladium(II) dichloride, tetrakis(triphenylphosphine)palladium, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2), and a palladium acetate-bis(diphenylphosphino)ferrocene composition, wherein the palladium acetate-bis(diphenylphosphino)ferrocene is a palladium acetate (1.00 eq)-bis(diphenylphosphino)ferrocene (dppf, 2.00 eq) composition.

[0027] In some embodiments, the base is selected from one or any combination of potassium acetate, tripotassium phosphate, and triethylamine.

[0028] In some embodiments, the boron reagent is selected from one or any combination of pinacol borane (12-1), isopropyl pinacol borate (12-2), and biboronic acid pinacol ester (12-3).

[0029] The corresponding reaction equation is as follows: .

[0030] In some embodiments, the solvent for the reaction is selected from toluene, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether (DME), N , N - one or any combination of dimethylformamide (DMF) and dimethyl sulfoxide.

[0031] In some embodiments, N -(2-Bromo-4-fluorophenyl)-3-difluoromethyl-1-methylpyrazole-4-carboxamide (11) reacts with a boron reagent in a solvent at a certain temperature, and the reaction temperature is 20 ℃~90 ℃.

[0032] In some embodiments, based on the amount of 3-fluoro-6-aminophenylboronic acid pinacol ester (9) being 1.0, the amounts of pinacol borane and isopropyl pinacol borate are 2.4-5.0, the amount of biboronic acid pinacol ester is 1.2-2.5, and the amount of the catalyst is 1% mol~6% mol.

[0033] Regarding step S2: The synthesized intermediate 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) was reacted with a carbon-14 labeled radioactive material in a one-step process to obtain dichlorophenyl ring carbon-14 labeled bixafenthionine (A).

[0034] About dichlorophenyl ring carbon-14 labeled bixafen (A, N -[2-(3,4-dichloro[phenyl-U- 14 The chemical formula of [C6]phenyl]-4-fluorophenyl]-3-(difluoromethyl)-1-methylpyrazole-4-carboxamide) is as follows: .

[0035] The asterisks in (A) indicate the locations of radioactive isotope carbon-14 labeling.

[0036] Specifically, 3-(difluoromethyl)- N -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) and carbon-14 labeled 3,4-dichlorobromo[phenyl-U- 14 C6]benzene (13-1), carbon-14 labeled trifluoromethanesulfonic acid-3,4-dichloro[phenyl-U- 14 C6]phenyl ester (13-2) or carbon-14 labeled 3,4-dichloroiodo[phenyl-U- 14 C6] Any reagent of benzene (13-3) is dissolved in a solvent and reacted at a certain temperature. The reactant is cooled to room temperature and filtered and chromatographed to obtain dichlorophenyl ring carbon-14 labeled bixafenthionine (A).

[0037] When the dichlorophenyl ring carbon-14 labeled bixafen (A) is synthesized, the corresponding reaction equation is as follows: .

[0038] In this case, the asterisk in the reaction equation indicates the labeling position of the radioactive isotope carbon-14.

[0039] In some embodiments, the inert gas is selected from dry argon, argon.

[0040] In some embodiments, the catalyst is selected from one or any combination of tetrakis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), bis(triphenylphosphine)dichloropalladium(II), and palladium acetate-bis(diphenylphosphino)ferrocene combination.

[0041] In some embodiments, the base is selected from one or any combination of potassium carbonate, sodium carbonate, tripotassium phosphate, and potassium acetate.

[0042] In some embodiments, the solvent is selected from N , N -dimethylformamide, N-Methyl-2-pyrrolidone (NMP), 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, dimethyl sulfoxide, toluene or any combination thereof.

[0043] In some embodiments, the reaction temperature is 20°C to 110°C.

[0044] In some embodiments, 3,4-dichlorobromo[phenyl-U- 14 C6]benzene (13-1), carbon-14 labeled trifluoromethanesulfonic acid-3,4-dichloro[phenyl-U- 14 C6]phenyl ester (13-2) or carbon-14 labeled 3,4-dichloroiodo[phenyl-U- 14 C6] benzene (13-3) is used in an amount of 1.0, 3-(difluoromethyl)- N The amount of 4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) is 1.0-3.0, the amount of the base is 3.0-4.0, and the amount of the catalyst is 3% mol-8% mol.

[0045] In the second aspect, the present invention provides a dichlorophenyl ring carbon-14 labeled bixafen prepared according to the preparation method of dichlorophenyl ring carbon-14 labeled bixafen mentioned in the first aspect. Dichlorophenyl ring carbon-14 labeled bixafen [ N -[2-(3,4-dichloro[phenyl-U- 14 C6]phenyl)-4-fluorophenyl]-3-(difluoromethyl)-1-methylpyrazole-4-carboxamide], the chemical formula of which is shown in the following formula (A): .

[0046] Compared with the existing technology, this technical solution has the following characteristics and beneficial effects: ① The method for preparing radioisotope carbon-14 labeled bixafen proposed in this scheme involves only one step of reaction involving the radioisotope carbon-14 labeled raw material, resulting in a high total radiochemical yield of the target product, low consumption of radioisotope carbon-14 labeled raw material, low generation of radioactive waste, and low cost; ② The entire process of the preparation method of radioactive isotope carbon-14 labeled bixafenthion proposed in this scheme involves only one radioactive reaction, and the radiation operation cycle is short, so the operator is exposed to the radiation site for a short time and the personnel safety risk is low.

[0047] ③ The carbon-14 labeled bixafen is prepared by the preparation method of radioactive isotope carbon-14 labeled bixafen proposed in this plan, and is used as a radioactive tracer to conduct metabolic test studies of the fungicide in crops, soil-water systems and livestock and poultry in accordance with the radioisotope tracer method specified in the national pesticide metabolism test guidelines, to provide metabolic test data for safety evaluation of the fungicide for registration with the Pesticide Testing Institute of the Ministry of Agriculture and Rural Affairs. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The present invention is a synthetic route diagram for synthesizing bixafen starting from the dichlorobenzene ring end in the prior art.

[0049] Figure 2 The present invention is a synthetic route diagram for synthesizing bixafen starting from the pyrazole ring end in the prior art.

[0050] Figure 3 It is the intermediate 3-(difluoromethyl)- N H NMR spectrum of -[4-fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10).

[0051] Figure 4 This is the H NMR spectrum of bixafen (A) labeled with carbon-14 on a dichlorophenyl ring.

[0052] Figure 5 This is the mass spectrum of bixafen (A) labeled with carbon-14 on a dichlorophenyl ring.

[0053] Figure 6 This is the radioactive chromatogram of bixafen (A) labeled with carbon-14 on a dichlorophenyl ring. DETAILED DESCRIPTION

[0054] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention are within the scope of protection of the present invention.

[0055] The following describes the embodiments of the present invention through specific examples. Those skilled in the art will readily understand the other advantages and benefits of the present invention from the disclosure herein. The present invention may also be implemented or applied through various other specific embodiments, and the details in this specification may be modified or altered based on different viewpoints and applications without departing from the spirit of the present invention.

[0056] Example 1

[0057] Under argon protection at room temperature, 3-fluoro-6-aminophenylboronic acid pinacol ester (9, 237 mg, 1.00 mmol), 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (5-1, 213 mg), 1-hydroxybenzotriazole (HOBt, 162 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 230 mg) and N , N -Diisopropylethylamine (DIPEA, 630 μL) was dissolved in anhydrous N , N -dimethylformamide (5.0 mL). Stir at room temperature for 15 h and the reaction is complete. Water (50 mL) is added to the reaction system, and the resulting mixture is extracted with ethyl acetate (60 mL), washed sequentially with saturated ammonium chloride solution (50 mL) and 10% sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, desolvated under reduced pressure, and subjected to silica gel flash column chromatography to obtain the target compound 3-(difluoromethyl)- N -[4-fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10, 367 mg, 93%), as Figure 3 As shown, the obtained 3-(difluoromethyl)- N The NMR spectrum data of -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide are: 1 H NMR (500 MHz, DMSO- d 6) δ 11.73 (s, 1H), 8.66 (s,1H), 7.32 – 7.02 (m, 4H), 3.99 (s, 3H), 1.25 – 1.11 (m, 12H). ESI-MS m / z : 396[M+H] + .

[0058] Example 2:

[0059] Under argon protection, 3-fluoro-6-aminophenylboronic acid pinacol ester (9, 237 mg), 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride (5-2, 452 mg), and anhydrous triethylamine (450 μL) were dissolved in dichloromethane (DCM, 10 mL), heated to gentle reflux, and stirred for 3 h to complete the reaction. Water (60 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (80 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to silica gel flash column chromatography to obtain the target product (10, 354 mg, 90%). The obtained product 10 1The results of H NMR and ESI-MS analysis were consistent with those of the target product in Example 1.

[0060] Example 3:

[0061] Under argon protection at 0°C, 3-fluoro-6-aminophenylboronic acid pinacol ester (9, 237 mg) and 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid ethyl ester (5-3, 306 mg) were added to anhydrous tetrahydrofuran (THF, 10 mL). Then, sodium bis(trimethylsilyl)amide (NaHMDS, 1 M solution in tetrahydrofuran; 1.5 mL) was slowly added. The mixture was naturally warmed to room temperature and stirred for 3 hours. Water (60 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (80 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to silica gel flash column chromatography to obtain the target product, 3-(difluoromethyl)- N -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10, 284 mg, 72%). The obtained product 10 1 The results of H NMR and ESI-MS analysis were consistent with those of the target product in Example 1.

[0062] Example 4:

[0063] Under argon protection and room temperature, N -(2-bromo-4-fluorophenyl)-3-difluoromethyl-1-methylpyrazole-4-carboxamide (11, 313 mg), diboronic acid pinacol ester (12-3, 548 mg), potassium acetate (307 mg), Pd(dppf)Cl2 (33 mg) were dissolved in N , N -dimethylformamide (DMF, 5 mL), heated to 90 ℃ and stirred for 15 h. Water (60 mL) was added to the reaction system, and the reaction mixture was extracted with ethyl acetate (80 mL×3). The extract was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel flash column chromatography to obtain the target compound 3-difluoromethyl- N -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10, 278 mg, 78%), to obtain the target 3-difluoromethyl- N The analytical results of -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10, 278 mg, 78%) were consistent with those of the target product in Example 1. The data were: 1H NMR (500 MHz, DMSO- d 6) δ 11.73 (s, 1H), 8.66 (s,1H), 7.32 – 7.02 (m, 4H), 3.99 (s, 3H), 1.25 – 1.11 (m, 12H). ESI-MS m / z : 396[M+H] + .

[0064] Example 5:

[0065] Under argon protection and room temperature, 3,4-dichlorobromo[phenyl-U- 14 C6]benzene (13-1, 113 mg, 4.44E+7Bq), 3-(difluoromethyl)- N 4-[4-Fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10, 276 mg, 0.70 mmol), potassium acetate (158 mg, 1.50 mmol), and Pd(dppf)Cl2 (26 mg, 0.035 mmol) were dissolved in anhydrous DMF (5 mL), heated to 90°C, and stirred for 12 h. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL x 6). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, desolvated under reduced pressure, and purified by silica gel flash column chromatography to obtain dichlorophenyl ring carbon-14 labeled bixafen (A, 178 mg, 3.82E+7 Bq, 86%). The NMR spectrum of the obtained dichlorophenyl ring carbon-14 labeled bixafen was shown in Figure 1. Figure 4 As shown, it can be seen 1 H NMR (500 MHz, DMSO- d 6) δ 9.73 (s,1H), 8.22 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.67 – 7.62 (m, 1H), 7.46 (dd, J =8.7, 5.5 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.36 – 7.26 (m, 2H), 7.18 –7.05 (m, 1H), 3.92 (s, 3H). ESI-MS m / z : 414[M+H] + , 416[M+2+H] + , the mass spectrum of dichlorophenyl ring carbon-14 labeled bixafen (A) is obtained as follows Figure 5 As shown, the radioactive chromatogram is Figure 6 shown.

[0066] Example 6:

[0067] Under argon protection, 3,4-dichloro[phenyl-U-trifluoromethanesulfonic acid] 14 C6]phenyl ester (13-2, 148 mg, 4.81E+7 Bq), 3-(difluoromethyl)- N 4-[4-Fluoro-2-(pinacol boronate)phenyl]-1-methylpyrazole-4-carboxamide (10, 237 mg) and potassium phosphate (340 mg) were mixed with dry dioxane (10 mL) previously degassed with argon bubbling and stirred for 10 minutes. Tetrakis(triphenylphosphine)palladium (31 mg) was added, and the mixture was heated to 90°C and stirred at this temperature for 18 hours. The reaction mixture was cooled to room temperature, filtered through a celite pad, desolvated under reduced pressure, and purified by silica gel flash column chromatography to obtain dichlorophenyl ring carbon-14-labeled bixafen (A, 186 mg, 4.33E+7 Bq, 90%). 1 H NMR (500 MHz, DMSO- d 6) δ 9.72 (s, 1H), 8.22 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.67 – 7.62 (m, 1H), 7.46 (dd, J = 8.7, 5.5 Hz,1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.36 – 7.26 (m, 2H), 7.16 – 7.05 (m, 1H), 3.91 (s, 3H). ESI-MS m / z : 414[M+H] + , 416[M+2+H] + .

[0068] This scheme comprehensively considers the availability and cost of starting radioisotope synthesis materials, post-treatment of radioactive reactions, product purification, total radiochemical yield, operational safety, and the amount of radioactive waste generated during the research and development process. A method for labeling the intermediate 3-(difluoromethyl)- N A method for preparing -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) and a method for preparing dichlorophenyl ring carbon-14 labeled bixafenthionine in a one-step method using the intermediate.

[0069] It is understood that the term "one" should be understood as "at least one" or "one or more", that is, in one embodiment, the number of an element may be one, while in another embodiment, the number of the elements may be multiple, and the term "one" should not be understood as a limitation on the quantity.

[0070] The present invention is not limited to the above-mentioned optimal implementation mode. Anyone can derive other forms of products under the inspiration of the present invention. However, no matter what changes are made in the shape or structure, any technical solution that is the same or similar to that of the present application falls within the scope of protection of the present invention.

Claims

1. A method for preparing dichlorobenzene ring carbon-14 labeled bixafen, characterized in that: The following steps are involved: S1: Preparation of 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide: Under the protection of inert gas, 3-fluoro-6-aminophenylboronic acid pinacol ester and 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid, 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride or 1-methyl-3-difluoromethylpyrazole-4-carboxylate are mixed in an organic solvent and a condensation agent, a catalytic activator and a base are added to react to obtain 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide; Or, under the protection of inert gas, in the presence of catalyst and base, N -(2-bromo-4-fluorophenyl)-3-difluoromethyl-1-methylpyrazole-4-carboxamide reacts with a boron reagent in a solvent at a certain temperature to obtain 3-(difluoromethyl)- N -[4-Fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide; S2: Preparation of dichlorophenyl ring carbon-14 labeled bixafen; Under the protection of inert gas, in the presence of a catalyst and a base, 3-(difluoromethyl)- N -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide and carbon-14 labeled 3,4-dichlorobromo[phenyl-U- 14 C6] benzene, carbon-14 labeled trifluoromethanesulfonic acid-3,4-dichloro[phenyl-U- 14 C6]phenyl ester or carbon-14 labeled 3,4-dichloroiodo[phenyl-U- 14 C6] Any reagent of benzene is dissolved in a solvent and reacted at a certain temperature to obtain dichlorobenzene ring carbon-14 labeled bixafenthrin.

2. The method for preparing dichlorobenzene ring carbon-14 labeled bixafen according to claim 1, characterized in that: The condensing agent in step S1 is selected from one or any combination of dicyclohexylcarbodiimide, diisopropylcarbodiimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; the catalytic activator is one of an acylation catalyst or an activator selected from 4-lutidine, 4-pyrrolidinopyridine, 1-hydroxybenzotriazole, 2-(7-azobenzotriazole)- N , N , N′ , N′ -tetramethyluronium hexafluorophosphate) or (ethyl 2-oximino-cyanoacetate)- N , N - one or any combination of dimethyl-morpholinourea hexafluorophosphate.

3. The method for preparing dichlorobenzene ring carbon-14 labeled bixafen according to claim 1, characterized in that: When 3-fluoro-6-aminophenylboronic acid pinacol ester is mixed with 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid in an organic solvent and a condensing agent, a catalyst activator and a base are added to react, the base is selected from triethylamine, diisopropylethylamine, N -Methylmorpholine, N -methyl piperidine or any combination thereof; the organic solvent is selected from dichloromethane, N , N -dimethylformamide or any combination thereof, and the reaction temperature is -5°C to 50°C.

4. The method for preparing dichlorobenzene ring carbon-14 labeled bixafen according to claim 1, characterized in that: When 3-fluoro-6-aminophenylboronic acid pinacol ester reacts with 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride, the base is selected from sodium carbonate, triethylamine, diisopropylethylamine, N -Methylmorpholine, N -methylpiperidine, pyridine or any combination thereof; the organic solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether or toluene or any combination thereof, and the reaction temperature is 20°C to 80°C.

5. The method for preparing dichlorobenzene ring carbon-14 labeled bixafen according to claim 1, characterized in that, When 3-fluoro-6-aminophenylboronic acid pinacol ester reacts with 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid ethyl ester, the base is selected from one or any combination of sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide; the organic solvent is an ether solvent selected from one or any combination of tetrahydrofuran, 2-methyltetrahydrofuran, and cyclopentyl methyl ether, and the reaction temperature is 0°C to 40°C.

6. The method for preparing dichlorobenzene ring carbon-14 labeled bixafen according to claim 1, characterized in that: The catalyst is selected from one or any combination of bis(triphenylphosphine)palladium dichloride (II), tetrakis(triphenylphosphine)palladium, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (II), palladium acetate-bis(diphenylphosphino)ferrocene composition, and the boron reagent is selected from one or any combination of pinacol borane, isopropyl pinacol borate and biboric acid pinacol ester.

7. The method for preparing dichlorobenzene ring carbon-14 labeled bixafen according to claim 1, characterized in that: The catalyst in step S2 is selected from one or any combination of tetrakis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis(triphenylphosphine)dichloropalladium(II), and palladium acetate-bis(diphenylphosphino)ferrocene composition, and the base is selected from one or any combination of potassium carbonate, sodium carbonate, tripotassium phosphate, and potassium acetate.

8. The method for preparing dichlorobenzene ring carbon-14 labeled bixafen according to claim 1, characterized in that: The chemical formula of dichlorobenzene ring carbon-14 labeled bixafen is shown in formula (A): , * in the figure indicates the position of carbon-14 labeling.

9. The method for preparing dichlorobenzene ring carbon-14 labeled bixafen according to claim 1, characterized in that: Carbon-14 labeled 3,4-dichlorobromo[phenyl-U- 14 C6]benzene (13-1), carbon-14 labeled trifluoromethanesulfonic acid-3,4-dichloro[phenyl-U- 14 C6]phenyl ester (13-2) or carbon-14 labeled 3,4-dichloroiodo[phenyl-U- 14 C6] benzene (13-3) is used in an amount of 1.0, 3-(difluoromethyl)- N The amount of -[4-fluoro-2-(pinacol borate)phenyl]-1-methylpyrazole-4-carboxamide (10) is 1.0-3.0, and the amount of the base is 3.0-4.

0.

10. A dichlorobenzene ring carbon-14 labeled bixafen, characterized in that: The preparation method of dichlorobenzene ring carbon-14 labeled bixafen is prepared according to any one of claims 1 to 9, wherein the chemical formula of dichlorobenzene ring carbon-14 labeled bixafen is shown in formula (A): , * in the figure indicates the position of carbon-14 labeling.

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