A radioisotope carbon-14 labeled flonicamid and its synthesis method

Abstract

The present scheme provides a method for synthesizing radioactive isotope carbon-14 labeled flonicamid, in which the radioactive isotope carbon-14 is labeled on the pyridine ring in the flonicamid molecule, and carbon-14 labeled barium carbonate is used as a radioactive isotope raw material, and carbon-14 carbon dioxide is released by reacting with concentrated sulfuric acid, and the target product is synthesized through reduction, formylation, dehydration, substitution, cyclization, amide condensation and other reactions. The pyridine ring carbon-14 labeled flonicamid prepared by the present invention can be used as a tracer for tracing and other research on the plant antiviral agent flonicamid in plants, animals, soil and water bodies; at the same time, the method of the present invention provides a reference for the preparation of carbon-14-containing synthetic building blocks.

Description

Technical Field

[0001] The present invention relates to the field of radiochemical synthesis, and in particular to a radioactive isotope carbon-14 labeled flonicamid and a synthesis method thereof. Background Art

[0002] Flunic acid amide is a new type of low-toxic pyridinamide insect growth regulator insecticide. It can effectively control piercing-sucking mouthparts pests on a wide range of crops. It has a new mechanism of action on the target, has no effect on acetylcholinesterase and nicotinyl acetylcholine receptors, has a good neural effect and rapid antifeedant activity on aphids, and is particularly effective against aphids. The agent works by hindering the sucking action of pests. After the pests ingest the agent, they stop sucking quickly and finally die of starvation. According to the electronic analysis of insect sucking behavior, flunic acid amide can make the stylet tissue of sucking pests such as aphids unable to insert into plant tissues and is effective. It has the characteristics of strong systemic absorption and good conduction activity, low dosage, high activity, and long lasting effect. It has no cross-resistance with organophosphate, carbamate and pyrethroid pesticides, and has good ecological compatibility. It also has high activity against cotton aphids that resist organophosphate, carbamate and pyrethroids, and is also effective against some other piercing-sucking mouthparts pests.

[0003] At present, in the research field of flonicamid, the discussion on its absorption, distribution, transfer, residue in plants and its environmental behavior in water and soil is mainly limited to the detection of the parent compound using chromatography or chromatography-mass spectrometry. However, this detection method only focuses on the original form of flonicamid and rarely involves the detection of its metabolites / degradants. This has led to a lack of in-depth research on the metabolic process and environmental behavior of flonicamid. However, after entering the environment and plants, flonicamid will undergo a series of complex changes, and its metabolites / degradants may have different properties and behavior patterns from the parent compound. The impact of these products on various levels of the ecosystem may be no less than that of the parent compound itself. Therefore, it is particularly important to synthesize radioactive isotope-labeled flonicamid. Through the traceability of radioactive isotopes, it is possible to clearly monitor the process of flonicamid's absorption in the plant body, the subsequent distribution path in various tissues and organs, and the transfer dynamics during the plant growth cycle, thereby accurately grasping its complete metabolic process in the plant body; in exploring the residue problem of flonicamid, radioactive isotope labeling can also clearly distinguish the residues of the parent compound and its metabolites / degradants, avoiding misjudgment of the total residue amount and the degree of hazard due to the inability to accurately identify metabolites.

[0004] In summary, the synthesis of radioactive isotope-labeled flonicamid is a key measure to break through the current bottleneck of flonicamid research. It will provide strong technical support for our in-depth understanding of the metabolic process and environmental behavior of flonicamid, and promote related research to a more in-depth and comprehensive new stage. Summary of the invention

[0005] The purpose of the present invention is to provide a radioactive isotope carbon-14 labeled flonicamid and a synthesis method thereof, and successfully synthesize pyridine ring carbon-14 labeled flonicamid, which can be used as a tracer for tracing and other research on the plant antiviral agent flonicamid in plants, animals, soil and water.

[0006] To achieve the above objectives, the present technical solution provides a method for synthesizing flonicamid labeled with radioactive isotope carbon-14, comprising the following steps:

[0007] S1: Under the protection of inert gas, carbon dioxide labeled with carbon-14 is introduced into a reaction system containing a reducing agent and an alcohol reagent, and stirred for a period of time. After the reaction is completed, water is added to quench the reaction and the reaction solution is concentrated to obtain carbon-14 labeled formate;

[0008] S2: Under the protection of inert gas, a polar aprotic solvent is added to the carbon-14 labeled formate to dissolve it, and a halogenated alkane, an inorganic base and a molecular sieve are added to the dissolved solution, and the solution is stirred at -20°C to 50°C for a period of time, and then filtered to obtain a filtrate, and the filtrate is washed and extracted with EA, and then dried, filtered and concentrated to dryness to obtain carbon-14 labeled benzyl formate;

[0009] S3: Under the protection of inert gas, use dry halogenated alkane to dissolve carbon-14 labeled benzyl formate, add lipid substrate and organic base to the dissolved solution, and add Lewis acid at -80℃~10℃, move to room temperature and stir for a period of time, then add water to quench and separate, use EA to extract the aqueous phase and backwash once with saturated brine, then dry, filter, concentrate to dryness, and perform rapid column chromatography to obtain 14 C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoic acid ethyl ester;

[0010] S4: Dissolve in a polar aprotic solvent under inert gas protection 14 C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoic acid ethyl ester was added with an inorganic base under ice-salt bath conditions and (3E)-4-amino-1,1,1-trifluorobut-3-en-2-one DMF solution was slowly added dropwise. After naturally heating for a period of time, saturated ammonium chloride was added to quench. The organic phase was extracted with EA, and the organic phases were combined and backwashed with brine and dried, filtered, concentrated to dryness, and flash column chromatography was performed to obtain 14C-(E)-ethyl 3-((E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)acrylate;

[0011] S5: Under the protection of inert gas, use a dry alcohol solution to dissolve the crude target product, add the first inorganic base and stir at -10°C~100°C for a period of time, then add the second inorganic base aqueous solution and stir at 10°C~100°C for a period of time. After the reaction is completed, concentrate the alcohol solution and dilute with water, extract with DCM and adjust the pH of the aqueous phase to 1-2 with 6M hydrochloric acid solution, extract the aqueous phase with EA, combine the EA phase, dry, and concentrate to dryness to obtain 14 C-4-(trifluoromethyl)nicotinic acid;

[0012] S6: Dissolve with dry alkyl halide under inert gas protection 14 C-4-(trifluoromethyl)nicotinic acid, aminoacetonitrile hydrochloride, organic base and organic synthesis reagent were added under ice-salt bath and naturally heated to react overnight, water was added to dilute the reaction system and then extracted with DCM, the organic phases were combined and dried, concentrated to dryness, and flash column chromatography was performed to obtain 14 C-flubencarb.

[0013] This scheme provides a method for synthesizing radioisotope carbon-14 labeled flonicamid. In this scheme, carbon-14 is labeled on the pyridine ring of flonicamid. The corresponding chemical formula of radioisotope carbon-14 labeled flonicamid is shown in the following formula (I), wherein the asterisk represents the carbon-14 labeling position:

[0014] .

[0015] The synthesis method of radioactive isotope carbon-14 labeled flonicamid selects the pyridine ring in the flonicamid molecule as the labeling position, uses carbon-14 labeled barium carbonate as a radioactive isotope raw material to react with concentrated sulfuric acid to release carbon-14 labeled carbon dioxide, converts a carbon-14 labeled carbon dioxide reducing agent into a carbon-14 labeled formate, converts a haloalkane into a formylation agent of a haloalkane under alkaline conditions, introduces carbon-14 into the carbonyl α position by utilizing the guiding effect of the carbonyl α position, and then utilizes (3E)-4-amino-1,1,1-trifluorobut-3-ene to obtain the radioactive isotope raw material. The strong nucleophilicity of the amino group in the -2-ketone completes the substitution reaction, and self-cyclizes under alkaline conditions to generate 4-trifluoromethylnicotinic acid with a carbon-14 labeled pyridine ring, which is then reacted with aminoacetonitrile hydrochloride through a condensing agent to obtain a carbon-14 labeled flonicamid product, and finally a pyridine ring carbon-14 labeled flonicamid is prepared, and the molar activity range of the marker is 1.0~57mCi / mmol; the chemical purity and radiochemical purity are both greater than 98%, and it can be used as a tracer for tracing and other studies of the plant antiviral agent flonicamid in plants, animals, soil and water.

[0016] Specifically, in step S1:

[0017] Using carbon-14 labeled barium carbonate as an isotope raw material, the carbon-14 labeled barium carbonate is reacted with concentrated sulfuric acid to obtain carbon-14 labeled carbon dioxide, wherein the molar activity of the carbon-14 labeled barium carbonate is 1.0~57 mCi / mmol.

[0018] The reducing agent in step S1 is selected as any one or a combination of two or more of calcium borohydride, sodium borohydride, and potassium borohydride, and the alcohol agent is selected as any one or a combination of two or more of methanol, ethanol, propanol, and isopropanol. Preferably, the reducing agent is selected as sodium borohydride, and the alcohol agent is selected as methanol. In this case, the formate obtained is sodium formate, and the corresponding reaction equation is as follows:

[0019] .

[0020] In some specific embodiments, carbon-14 labeled carbon dioxide is introduced into a reaction system containing a reducing agent and an alcohol reagent and vigorously stirred for 1 to 24 hours. After the reaction is completed, water is added to quench the reaction, and then the reaction solution is concentrated to dryness to obtain carbon-14 labeled formate.

[0021] The carbon-14 labeled formate prepared in step S1 of this scheme can be directly used in the reaction of step S2 without purification.

[0022] In step S2:

[0023] The carbon-14 labeled formate is converted into the formylation reagent of the alkyl halide by an alkyl halide under alkaline conditions.

[0024] The polar aprotic solvent in step S2 is selected from any one of DMSO, DMF, THF or a combination of two or more thereof. Preferably, the polar aprotic solvent is DMF.

[0025] The alkyl halide in step S2 is selected from any one or a combination of two or more of benzyl chloride, benzyl bromide, benzyl iodide, ethyl chlorobenzene, ethyl bromobenzene, ethyl iodobenzene, 1-iodo-3-phenylpropane, 1-chloro-3-phenylpropane, 1-bromo-3-phenylpropane and 4-bromomethylbiphenyl, the inorganic base is selected from any one or a combination of two or more of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and the molecular sieve is selected from any one or a combination of two or more of 3A molecular sieve, 4A molecular sieve, and 5A molecular sieve.

[0026] In some preferred embodiments, the alkyl halide is 4-bromomethylbiphenyl, the inorganic base is potassium carbonate, and the molecular sieve is preferably 4A molecular sieve.

[0027] Specifically, alkyl halide, inorganic base and molecular sieve are added to the dissolved solution and stirred at -20°C to 50°C for 1 to 12 hours, and then filtered to obtain a filtrate, and the filtrate is washed with EA to obtain a washing liquid, and the washing liquid is diluted with water and then extracted with EA three times and backwashed with saturated brine twice, dried, filtered, and concentrated to dryness to obtain carbon-14 labeled benzyl formate. The corresponding carbon-14 labeled benzyl formate has a structural formula as shown in the following formula (II):

[0028] .

[0029] In step S3:

[0030] By utilizing the directing effect of the carbonyl α position, carbon-14 is introduced into the carbonyl α position of the formylation reagent of the alkyl halide to obtain 14 C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoic acid ethyl ester.

[0031] The alkyl halide in step S3 is selected from any one or a combination of two or more of dichloromethane, chloroform, carbon tetrachloride, and dichloroethane, preferably dichloromethane.

[0032] The lipid substrate in step S3 is selected from any one or a combination of two or more of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, and benzyl acetate, preferably ethyl acetate.

[0033] The organic base in step S3 is selected from any one or a combination of two or more of diisopropylethylamine, DBU, and triethylamine, preferably triethylamine.

[0034] The Lewis acid in step S3 is selected from any one or a combination of two or more of aluminum trichloride, boron trifluoride, ferric chloride, titanium tetrachloride, and tetraethyl titanate, preferably titanium tetrachloride.

[0035] Specifically, a dry alkyl halide is used to dissolve carbon-14 labeled benzyl formate, a lipid substrate and an organic base are added to the dissolved solution, and a Lewis acid is added at -80°C to 10°C, the mixture is stirred at room temperature for 1 to 12 hours, water is added to the reaction solution to quench the mixture, and the aqueous phase is extracted twice with EA and backwashed once with saturated brine, dried, filtered, concentrated to dryness, and subjected to rapid column chromatography to obtain 14 The chemical formula of ethyl C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoate is shown in the following formula (III):

[0036] .

[0037] In step S4:

[0038] Taking advantage of the strong nucleophilicity of the amino group in (3E)-4-amino-1,1,1-trifluorobut-3-en-2-one, 14C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoic acid ethyl ester completes the substitution reaction to obtain 14 C-(E)-ethyl 3-((E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)acrylate.

[0039] Specifically, the polar aprotic solvent in step S4 is selected from any one or a combination of two or more of DMSO, DMF, and THF, preferably DMF.

[0040] The inorganic base in step S4 is selected from any one of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium hydride, or a combination of two or more thereof, preferably sodium hydride.

[0041] Specifically, a polar aprotic solvent is used to dissolve 14 C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoic acid ethyl ester, add inorganic base under ice-salt bath conditions and slowly drop (3E)-4-amino-1,1,1-trifluorobut-3-en-2-one DMF solution, naturally heat the reaction for 5-24 hours, add saturated ammonium chloride to quench, use EA to extract the organic phase three times, combine the organic phases, backwash with brine and dry, filter, concentrate to dryness, and obtain by rapid column chromatography 14 C-(E)-3-((E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)ethyl acrylate, the chemical formula is as follows (IV):

[0042] .

[0043] In step S5:

[0044] The alcohol solution in step S5 is selected from one of methanol, ethanol, propanol and isopropanol, preferably methanol.

[0045] The first inorganic base in step S5 is selected from any one of sodium methoxide, sodium ethoxide, and potassium tert-butoxide, or a combination of two or more thereof, preferably sodium methoxide.

[0046] The inorganic base in step S5 is selected from any one or a combination of two or more of potassium hydroxide, sodium hydroxide and lithium hydroxide, preferably sodium hydroxide.

[0047] In some embodiments, after adding the first inorganic base, stirring is carried out at -10°C to 100°C for 1 to 24 hours, and after adding the aqueous solution of the second inorganic base, stirring is carried out at 10°C to 100°C for 1 to 24 hours.

[0048] In some embodiments, the alcohol solution is concentrated and diluted with water, extracted twice with DCM, and the pH value of the aqueous phase is adjusted to 1-2 with 6M hydrochloric acid solution, and the aqueous phase is extracted 4 times with EA, the EA phases are combined, dried, and concentrated to dryness to obtain 14C-4-(Trifluoromethyl)nicotinic acid, 14 C-4-(trifluoromethyl)nicotinic acid is represented by the following formula (V):

[0049] .

[0050] In step S6:

[0051] The alkyl halide in step S6 is selected from any one or a combination of two or more of dichloromethane, chloroform, carbon tetrachloride, and dichloroethane, preferably dichloromethane.

[0052] The organic base in step S6 is selected from any one or a combination of two or more of diisopropylethylamine, DBU, and triethylamine, preferably triethylamine.

[0053] The organic synthesis reagent in step S6 is selected from any one or a combination of two or more of HOBT, HBTU, TBTU, HATU, and EDCI, preferably HATU.

[0054] Specifically, the target product is dissolved in dry alkyl halide, aminoacetonitrile hydrochloride is added, an organic base and an organic synthesis reagent are added in an ice-salt bath, and the temperature is naturally raised to react overnight, water is added to dilute the reaction system, and then DCM is used for extraction, the organic phases are combined and dried, concentrated to dryness, and rapid column chromatography is performed to obtain 14 C-flubencarb, the structural formula is shown in the following formula (I):

[0055] .

[0056] In a second aspect, the present invention provides a radioactive isotope carbon-14 labeled fluphenazine, which is synthesized according to the above-mentioned synthesis method, and has a structural formula as shown in the following formula (I):

[0057] .

[0058] Compared with the prior art, the technical scheme has the following characteristics and beneficial effects: This scheme selects the pyridine ring in the flubenzonamide molecule as the labeling position, uses carbon-14 labeled barium carbonate as the radioactive isotope raw material, releases carbon-14 carbon dioxide by reaction with concentrated sulfuric acid, and synthesizes carbon-14 labeled pyridine ring flubenzonamide through reduction, formylation, dehydration, substitution, cyclization, amide condensation and other reactions. The synthesized carbon-14 labeled pyridine ring flubenzonamide has a determined labeling site, a high total yield, and high radiochemical purity and chemical purity. The nuclide carbon-14 is firmly labeled in the flubenzonamide molecule and is not easy to fall off, which can meet the requirements of tracing experiments in organisms and the environment. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 FIG. 1 is a radioactive chromatogram of flonicamid labeled with radioactive isotope carbon-14 according to an embodiment of the present invention.

[0060] FIG2 is a high performance liquid chromatogram of radioactive isotope carbon-14 labeled flonicamid in the present invention.

[0061] FIG3 is a mass spectrum of radioactive isotope carbon-14 labeled flonicamid in the present invention. DETAILED DESCRIPTION

[0062] The following will be combined with the accompanying drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0063] Those skilled in the art should understand that, in the disclosure of the present invention, the terms "longitudinal", "lateral", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside", etc., indicating the orientation or position relationship, are based on the orientation or position relationship shown in the drawings, which are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operate in a specific orientation. Therefore, the above terms should not be understood as limiting the present invention.

[0064] It is to be 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 element may be multiple, and the term "one" should not be understood as a limitation on the quantity.

[0065] Embodiment 1

[0066] The applicant team provides the synthesis steps of radioactive isotope carbon-14 labeled flonicamid:

[0067] Step S1: In an ice-water bath and nitrogen atmosphere, add concentrated sulfuric acid (5 mL) to 14 C-barium carbonate (598 mg, 3 mmol, 65.6 mCi / mmol), produced 14 C-carbon dioxide was introduced into the reaction system of sodium borohydride (137 mg, 3.6 mmol), methanol (346 mg, 10.8 mmol), and ethanol (15 mL), and stirred vigorously for 5 h. After the reaction, water (0.2 mL) was added to quench the reaction, and the reaction solution was transferred to a 100 mL round-bottom flask and concentrated to dryness to obtain a crude product. 14 C-Sodium formate does not need to be purified and is directly used in the next step. The reaction formula is as follows: ;

[0068] Step S2: Under nitrogen protection, DMF (10 mL) was added to the crude product obtained in the previous step to dissolve, and biphenylbenzyl bromide (1.11 g, 4.5 mmol), sodium carbonate (318 mg, 3 mmol) and molecular sieves (1.5 g) were added, stirred at 30 ° C (12 h), filtered, washed with EA, diluted with water (40 mL) and extracted with EA (20 mL) three times, backwashed with saturated brine (20 mL) twice, dried, filtered, concentrated to dryness, and the crude product was obtained. 14 C-benzyl formate is directly used in the next step reaction, and the reaction formula is as follows:

[0069] ;

[0070] Step S3: Under argon protection, 14 C-benzyl formate was dissolved in dry dichloromethane (10 mL), EA (327 mg, 3.7 mmol) and triethylamine (470 mg, 4.66 mmol) were added, and a dichloromethane solution of titanium tetrachloride (705 mg, 3.7 mmol, 0.75 M) was added dropwise at -15 °C for 12 minutes, and the mixture was stirred at room temperature for 1.5 h. Then, water (25 mL) was added to the reaction solution to quench the mixture, and the layers were separated. The aqueous phase was extracted twice with EA (20 mL), backwashed once with saturated brine (20 mL), dried, filtered, concentrated to dryness, and purified on a 5 cm diameter, 20 g (300-400 mesh) silica gel column. The eluents were PE (100 mL), DCM:PE=1:8 (200 mL), and DCM:PE=1:6 (1 L). The flow rate was 1 mL / s. The effluent of DCM:PE=1:6 was collected and concentrated to dryness to obtain 14 C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoic acid ethyl ester (360 mg, 1.3 mmol, 42% yield), the reaction formula is as follows:

[0071] ;

[0072] Step S4: Dissolve the mixture in DMF (5 mL) under nitrogen. 14 C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoic acid ethyl ester (360 mg, 1.3 mmol) was added with sodium hydride (62 mg, 1.56 mmol) under ice-salt bath conditions, and (3E)-4-amino-1,1,1-trifluorobut-3-en-2-one DMF solution (217 mg, 1.56 mmol, 1 M) was slowly added dropwise. The reaction was naturally heated for 12 h, and saturated ammonium chloride (10 mL) was added to quench. EA (15 mL) was extracted three times, and the organic phases were combined and backwashed twice with brine (15 mL), dried, filtered, concentrated to dryness, and flash column chromatography was performed to obtain 14C-(E)-3-((E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)ethyl acrylate, the reaction formula is as follows: ;

[0073] Step S5: Under nitrogen protection, use dry methanol (10 mL) to dissolve the product of the previous step, add sodium methoxide methanol solution (2.4 mL, 10 mmol, 5.4 M), stir at 70 ° C for 3 h, then add sodium hydroxide (104 mg, 2.6 mmol, 1 M) aqueous solution to the system, stir at 50 ° C for 2 h, after the reaction is completed, concentrate the methanol solution at 40 ° C, dilute with water (20 mL), extract with DCM (20 mL) twice, adjust the aqueous phase pH to 1-2 with 6 M hydrochloric acid solution, extract the aqueous phase with EA (20 mL) 4 times, combine the EA phase, dry, and concentrate to dryness to obtain 14 C-4-(Trifluoromethyl)nicotinic acid (149 mg, 0.77 mmol, 59% yield), reaction formula is as follows:

[0074] ;

[0075] Step S6: Under nitrogen protection, dissolve the solution obtained in the previous step with DCM (25 mL). 14 C-4-(trifluoromethyl)nicotinic acid, aminoacetonitrile hydrochloride (86 mg, 0.92 mmol), triethylamine (194 mg, 1.9 mmol) and HATU (351 mg, 0.92 mmol) were added under ice-salt bath, and the temperature was naturally raised to react for 12 hours. The reaction system was quenched with 10% sodium bicarbonate aqueous solution (20 mL), extracted twice with DCM (20 mL), extracted twice with EA (20 mL), and the organic phases were combined and dried, concentrated to dryness, and purified by a 5 cm diameter, 20 g (300-400 mesh) silica gel column, the eluent was PE (100 mL), DCM:MeOH = 100:1 (100 mL), DCM:MeOH = 80:1 (1 L), the flow rate was 1 mL / s, and the effluent of DCM:MeOH = 80:1 was collected and concentrated to dryness to obtain 14 C-flubencarb (128 mg, 0.55 mmol, 72% yield), the reaction formula is as follows: .

[0076] The prepared sample of Example 1 14 The radioactive chromatogram of C-flubenzuronamide was measured. Figure 1 ,like Figure 1 The radiochemical purity was 99.83%; the HPLC analysis showed Figure 2 ,like Figure 2 The chemical purity was 99.86% (254 nm) and the mass spectrometry test showed that Figure 3 ,like Figure 3 The mass spectrum shown is ESI-MS (+) = 231.98.

[0077] The present invention is not limited to the above-mentioned optimal implementation mode. Anyone can derive other various forms of products under the inspiration of the present invention. However, no matter what changes are made in the shape or structure, all technical solutions that are the same or similar to those of the present application fall within the protection scope of the present invention.

Claims

1. A method for synthesizing radioactive isotope carbon-14 labeled flonicamid, characterized in that: The following steps are involved: S1: Under the protection of inert gas, carbon dioxide labeled with carbon-14 is introduced into a reaction system containing a reducing agent and an alcohol reagent, and stirred for a period of time. After the reaction is completed, water is added to quench the reaction and the reaction solution is concentrated to obtain carbon-14 labeled formate; S2: Under the protection of inert gas, a polar aprotic solvent is added to the carbon-14 labeled formate to dissolve it, and a halogenated alkane, an inorganic base and a molecular sieve are added to the dissolved solution, and the solution is stirred at -20°C to 50°C for a period of time, and then filtered to obtain a filtrate, and the filtrate is washed and extracted with EA, and then dried, filtered and concentrated to dryness to obtain carbon-14 labeled benzyl formate; S3: Under the protection of inert gas, use dry halogenated alkane to dissolve carbon-14 labeled benzyl formate, add ester substrate and organic base to the dissolved solution, add Lewis acid at -80℃~10℃, move to room temperature and stir for a period of time, then add water to quench and separate, use EA to extract the aqueous phase and backwash once with saturated brine, then dry, filter, concentrate to dryness, and perform rapid column chromatography to obtain 14 C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoic acid ethyl ester; S4: Under the protection of inert gas, use a polar aprotic solvent to dissolve (2E)-3-[(4-phenyl)benzyloxy]prop-2-enoic acid ethyl ester (3- 14 C), sodium hydride was added under ice-salt bath conditions and (3E)-4-amino-1,1,1-trifluorobut-3-ene-2-one DMF solution was slowly added dropwise, the temperature was naturally raised for a period of time, saturated ammonium chloride was added to quench, the organic phase was extracted with EA, the organic phases were combined and backwashed with brine and dried, filtered, concentrated to dryness, and flash column chromatography was performed to obtain 14 C-(E)-3-((E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino); S5: Dissolve in dry alcohol solution under inert gas protection 14 C-(E)-3-((E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino), add sodium methoxide methanol solution and stir for a period of time at -10°C~100°C, then add sodium hydroxide aqueous solution and stir for a period of time at 10°C~100°C. After the reaction is completed, concentrate the alcohol solution and dilute with water, extract with DCM and adjust the pH of the aqueous phase to 1-2 with 6M hydrochloric acid solution, extract the aqueous phase with EA, combine the EA phase, dry, and concentrate to dryness to obtain 14 C-4-(trifluoromethyl)nicotinic acid; S6: Dissolve with dry alkyl halide under inert gas protection 14 C-4-(trifluoromethyl)nicotinic acid, aminoacetonitrile hydrochloride, organic base and organic synthesis reagent were added under ice-salt bath and naturally heated to react overnight, water was added to dilute the reaction system and then extracted with DCM, the organic phases were combined and dried, concentrated to dryness, and flash column chromatography was performed to obtain 14 C-flubencarb.

2. The method for synthesizing radioactive isotope carbon-14 labeled flonicamid according to claim 1, characterized in that: In step S1, barium carbonate labeled with carbon-14 is used as an isotope raw material, and the barium carbonate labeled with carbon-14 is reacted with concentrated sulfuric acid to obtain carbon-14 labeled carbon dioxide, wherein the molar activity of the barium carbonate labeled with carbon-14 is 1.0-57 mCi / mmol.

3. The method for synthesizing radioactive isotope carbon-14 labeled flonicamid according to claim 1, characterized in that: In step S1, the reducing agent is selected as any one of calcium borohydride, sodium borohydride, and potassium borohydride, or a combination of two or more thereof, and the alcohol agent is selected as any one of methanol, ethanol, propanol, and isopropanol, or a combination of two or more thereof.

4. The method for synthesizing radioactive isotope carbon-14 labeled flonicamid according to claim 1, characterized in that: In step S2, the polar aprotic solvent is selected from any one or a combination of two or more of DMSO, DMF, and THF, the alkyl halide is selected from any one or a combination of two or more of benzyl chloride, benzyl bromide, benzyl iodide, ethyl chlorobenzene, ethyl bromobenzene, ethyl iodobenzene, 1-iodo-3-phenylpropane, 1-chloro-3-phenylpropane, 1-bromo-3-phenylpropane and 4-bromomethylbiphenyl, the inorganic base is selected from any one or a combination of two or more of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate, and the molecular sieve is selected from any one or a combination of two or more of 3A molecular sieve, 4A molecular sieve, and 5A molecular sieve.

5. The method for synthesizing radioactive isotope carbon-14 labeled flonicamid according to claim 1, characterized in that: The structural formula of carbon-14 labeled benzyl formate in step S2 is shown in the following formula (II): 。 6. The method for synthesizing radioactive isotope carbon-14 labeled flonicamid according to claim 1, characterized in that: In step S3, the alkyl halide is selected from any one or a combination of two or more of dichloromethane, chloroform, carbon tetrachloride, and ethylene dichloride; the ester substrate is selected from any one or a combination of two or more of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, and benzyl acetate; the organic base is selected from any one or a combination of two or more of diisopropylethylamine, DBU, and triethylamine; the Lewis acid is selected from any one or a combination of two or more of aluminum chloride, boron trifluoride, ferric chloride, titanium tetrachloride, and tetraethyl titanate; and the 14 The chemical formula of ethyl C-(2E)-3-[(4-phenyl)benzyloxy]prop-2-enoate is shown in the following formula (III): 。 7. The method for synthesizing radioactive isotope carbon-14 labeled flonicamid according to claim 1, characterized in that: In step S4, the polar aprotic solvent is selected from any one of DMSO, DMF, THF or a combination of two or more thereof, and the solvent obtained in step S4 is 14 The chemical formula of C-(E)-3-((E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)ethyl acrylate is shown in the following formula (IV): 。 8. The method for synthesizing radioactive isotope carbon-14 labeled flonicamid according to claim 1, characterized in that: In step S5, the alcohol solution is selected from any one of methanol, ethanol, propanol, isopropanol or a combination of two or more thereof, and the obtained 14 The structural formula of C-4-(trifluoromethyl)nicotinic acid is shown in the following formula (V): 。 9. The method for synthesizing radioactive isotope carbon-14 labeled flonicamid according to claim 1, characterized in that: In step S6, the alkyl halide is selected from any one or a combination of two or more of dichloromethane, chloroform, carbon tetrachloride, and ethylene dichloride, the organic base is selected from any one or a combination of two or more of diisopropylethylamine, DBU, and triethylamine, and the organic synthesis reagent is selected from any one or a combination of two or more of HOBT, HBTU, TBTU, HATU, and EDCI.

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