CN111689899A - Stable isotope labeled fipronil and its derivative and synthetic preparation method - Google Patents

Stable isotope labeled fipronil and its derivative and synthetic preparation method Download PDF

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CN111689899A
CN111689899A CN201910194926.1A CN201910194926A CN111689899A CN 111689899 A CN111689899 A CN 111689899A CN 201910194926 A CN201910194926 A CN 201910194926A CN 111689899 A CN111689899 A CN 111689899A
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fipronil
dichloro
stable isotope
trifluoromethylaniline
cyano
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CN111689899B (en
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邓晓军
古淑青
赵超敏
李优
陈武炼
王易
郭会
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Shanghai Anpu Experimental Technology Co ltd
TECHNICAL CENTRAL FOR ANIMALS PLANTS AND FOOD INSPECTION AND QUARANTINE SHANGHAI ENTRY-EXIT INSPECTION AND QUARANTINE BUREAU
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TECHNICAL CENTRAL FOR ANIMALS PLANTS AND FOOD INSPECTION AND QUARANTINE SHANGHAI ENTRY-EXIT INSPECTION AND QUARANTINE BUREAU
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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Abstract

The invention discloses three new compounds: stable isotope labeled fipronil and 2 derivatives thereof, and synthesis preparation methods thereof. The synthesis method uses stable isotope labeled p-trifluoromethylaniline-13C6The method is characterized in that a derivative is obtained through three steps of chemical reactions: 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6(ii) a Then the derivative is subjected to one-step oxidation reaction to obtain the stable isotope labeled fipronil-13C6And another derivative thereof: stable isotope labeled fipronil sulfone-13C6. The 3 compounds are synthesized and prepared for the first time, the chemical purity and the isotopic abundance of the 3 compounds reach more than 98 percent, and the 3 compounds have great innovation; and the subsequent internal standard substance can be used as an internal standard substance for developing a stable isotope internal standard method, and has potential market economic value.

Description

Stable isotope labeled fipronil and its derivative and synthetic preparation method
Technical Field
The invention relates to a stable isotope labeled compound and a synthetic preparation method thereof, in particular to a stable isotope labeled fipronil and a derivative and a synthetic preparation method thereof.
Background
Fipronil and its derivatives belong to the group of phenylpyrazole compounds, and are highly effective insecticides first developed by the French Roner-Planck company. It has a broad insecticidal spectrum and is harmless to crops, so that it has been widely used in agriculture and horticulture, and has been recommended by many agricultural specialists as one of the first-choice varieties to replace highly toxic organophosphorus pesticides. However, with further research by researchers, fipronil is found to be extremely unfriendly to the environment and to have an influence on butterflies, dragonflies and the like around crops, so that fipronil is prohibited in China from 10/1 in 2009. European union law also stipulates that fipronil is prohibited from being administered directly to domestic animals and must not be used in livestock in the human food industry chain. The world health organization indicates that liver, thyroid and kidney are damaged by eating food containing high concentrations of fipronil. Therefore, the detection of the residue of the medicine in food and the supervision thereof are urgent and necessary.
The traditional detection methods mainly comprise High Performance Liquid Chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (HPLC-MS), but the methods generally have the defects of low sensitivity, complicated method, semi-quantitative analysis and the like. The newly developed stable Isotope Dilution Mass Spectrometry (IDMS) adopts a stable Isotope labeled compound with the same molecular structure as a detected substance as an internal standard substance, uses a high resolution liquid chromatography-Mass Spectrometry (LC-MS) for detection, measures the ratio of ions with corresponding Mass numbers through a Mass spectrometer, and compares the ratio with the standard ratio to achieve the purpose of accurate quantification. The isotope internal standard can not only effectively reduce the deviation of the sample caused in the pretreatment step, but also eliminate the error brought by the instrument. The combination of the characteristic of stable isotope internal standard and the high sensitivity of LC-MS and the capability of processing complex samples, the chromatography-isotope dilution mass spectrometry technology is known as a standard quantitative method for measuring trace and trace organic matters, and the application is more and more extensive.
At present, the synthesis research of the stable isotope labeled fipronil and the derivative is few, and no commercial product exists. Therefore, no corresponding detection method using the fipronil and the derivative which are marked by stable isotopes as internal standards exists.
Disclosure of Invention
The invention aims to provide stable isotope labeled fipronil, derivatives thereof and a synthetic preparation method, the preparation process is simple, the product is easy to separate and purify, and the obtained target product has high chemical purity and isotope abundance.
The purpose of the invention can be realized by the following technical scheme:
fipronil labeled by stable isotope13C6Or fipronil sulfone-13C6Wherein, the fipronil-13C6The structural formula of (A) is as follows:
Figure BDA0001995525710000031
said fipronil sulfone-13C6The structural formula of (A) is as follows:
Figure BDA0001995525710000032
a stable isotope labeled fipronil derivative, wherein the structural formula is as follows:
Figure BDA0001995525710000033
a synthetic preparation method of fipronil and its derivatives marked by stable isotope includes the following steps: s1) stable isotope labeling of p-trifluoromethylaniline-13C6Reacting with a chlorinating reagent to prepare the stable isotope labeled 2, 6-dichloro-4-trifluoromethylaniline-13C6(ii) a S2) under the condition of mixed acidity, 2, 6-dichloro-4-trifluoromethylaniline-13C6Diazotizing, reacting with 2, 3-dicyano ethyl propionate to obtain the stable isotope labeling intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole-13C6(ii) a S3) reacting 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole-13C6Dissolving in organic solvent, adding dehydrating agent, reacting with trifluoromethyl sulfinyl chloride to obtain 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethyl thiopyrazole-13C6(ii) a S4) reacting 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6Dissolving and oxidizing to obtain the fipronil-containing material with stable isotope labeling13C6Or sulfoxaflor13C6。
Further: the chlorinating agent in the step S1) is N-bromosuccinimide, and the molar amount of the N-bromosuccinimide is p-trifluoromethylaniline-13C62-3 times of the reaction time, wherein the reaction temperature in the step S1) is controlled to be 20-30 ℃, and the reaction time is 2-4 hours.
Further: the chlorinating agent in the step S1) is hydrochloric acid-hydrogen peroxide; the mass percentage concentration of the hydrochloric acid is 10-15 percent, and the mass amount of the hydrochloric acid is p-trifluoromethylaniline-13C617-21 times of; the mass percentage concentration of the hydrogen peroxide is 25-30 percent, and the mass dosage is p-trifluoromethylaniline-13C61.5-2.5 times of the total weight of the composition,the reaction temperature in the step S1) is 50-60 ℃, and the reaction time is 2-3 hours.
Further: the step S2) is added with sodium nitrite to react with 2, 6-dichloro-4-trifluoromethylaniline-13C6Diazotizing, wherein the mixed acid in the step S2) is concentrated sulfuric acid and glacial acetic acid which are mixed in equal volumes, the molar ratio of the concentrated sulfuric acid to the sodium nitrite is 4-5, and the sodium nitrite and 2, 6-dichloro-4-trifluoromethylaniline-13C6The molar ratio of the ethyl 2, 3-dicyanopropionate to the 2, 6-dichloro-4-trifluoromethylaniline-13C6The molar ratio is 1.5-2.
Further: in the step S2), the initial reaction temperature is controlled to be 0-10 ℃, the reaction time is 15-30 minutes, and the subsequent reaction temperature is controlled to be 50-60 ℃, and the reaction time is 30-60 minutes.
Further: the organic solvent in the step 3) is anhydrous and does not react with the trifluoromethyl sulfinyl chloride, and the organic solvent is one or a mixture of more of 1, 2-dichloroethane, toluene, chloroform and 1, 2-dichloroethane.
Further: and in the step S3), the dehydrating agent is one or a mixture of more of phosphorus oxychloride, phosphorus trichloride and thionyl chloride.
Further: the trifluoromethyl sulfinyl chloride and the intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole-13C6The molar ratio of (A) to (B) is 1.1-1.5, the reaction temperature is 80-100 ℃, and the reaction time is 12-18 hours.
Further: the oxidant in the step S4) is one or a mixture of more of m-chloroperoxybenzoic acid, hydrogen peroxide and potassium peroxydisulfate.
Further: the step S4) is performed by controlling the oxidizing agent and 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6The molar ratio of the target product is 1.3-1.5, and the obtained target product is sulfoxide fipronil-13C6(ii) a Control of oxidant and 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6Has a large molar ratioAt 10, the obtained target product is fipronil sulfone-13C6Control the oxidant and the stable 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6The molar ratio of the target product is 1.5-10, and the obtained target product is fipronil-13C6With fipronil sulfone-13C6A mixture of (a).
Further: the reaction temperature in the step S4) is 20-60 ℃, and the reaction time is 4-8 hours.
Compared with the prior art, the invention has the following beneficial effects: the present invention provides 3 new stable isotope labeled compounds and their synthesis method. 2, 6-dichloro-4-trifluoromethylaniline-labeled with stable isotope13C6The derivative is synthesized by three steps of reactions as raw materials: stable isotope labeled 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6(formula 3 compound), then using the formula 3 compound as raw material, obtaining fipronil-containing agent by oxidation13C6And another derivative: fipronil sulfone-13C6The isotope atoms can not fall off in the reaction process of each step, and the utilization rate of the stable isotope atoms is high; the synthetic process is simple, the product is easy to separate and purify, and the chemical purity and the isotopic abundance of the obtained product both reach more than 98 percent. The 3 compounds are synthesized and prepared for the first time, and have great innovation; and the subsequent internal standard substance can be used as an internal standard substance for developing a stable isotope internal standard method, and has potential market economic value.
Drawings
FIG. 1 is a GC-MS graph of a compound of formula 3 according to the present invention;
FIG. 2 shows stable isotope labeled fipronil-13C6Comparing the liquid mass spectrum of the non-labeled fipronil with that of the non-labeled fipronil;
FIG. 3 shows stable isotope labeled fipronil sulfone-13C6A liquid mass spectrum comparison graph of non-labeled fipronil sulfone;
FIG. 4 shows the present inventionThe obtained stable isotope labeled fipronil-13C6Is/are as follows1H NMR spectrum;
FIG. 5 shows the stable isotope labeled fipronil-13C6Is/are as follows13C NMR spectrum;
FIG. 6 shows stable isotope labeled fipronil sulfone-13C6Is/are as follows1H NMR spectrum;
FIG. 7 shows stable isotope labeled fipronil sulfone-13C6Is/are as follows13C NMR spectrum;
FIG. 8 shows stable isotope labeled fipronil-13C6The high performance liquid chromatogram of (1);
FIG. 9 shows stable isotope labeled fipronil sulfone-13C6The high performance liquid chromatogram of (1).
Detailed Description
The invention is further described below with reference to the drawings and the examples.
The invention relates to three novel stable isotope labeled compounds and a synthesis preparation method thereof. Three new stable isotope labeled compounds are: 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6(hereinafter referred to as compound formula 3), 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfinylpyrazole-13C6(hereinafter abbreviated as fipronil-13C6) And 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfonylpyrazole-13C6(hereinafter referred to as fipronil sulfone-13C6). The structural formula of the three compounds is shown in the specification, wherein carbon atoms on benzene rings are13C atom:
Figure BDA0001995525710000071
s1) stable isotope labeling of p-trifluoromethylaniline-13C6Reacting with a chlorinating reagent to obtain stable isotope labeled 2, 6-dichloro-4-trifluoromethylaniline-13C6The structural formula is shown as formula 1, wherein carbon atoms on a benzene ring are13C atom:
Figure BDA0001995525710000081
s2) under the condition of mixed acidity, the stable isotope labeled 2, 6-dichloro-4-trifluoromethylaniline-13C6Diazotizing, reacting with 2, 3-dicyano propionic acid to obtain stable isotope labeling intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole-13C6The structural formula is shown as formula 2, wherein carbon atoms on a benzene ring are13C atom:
Figure BDA0001995525710000082
s3) the stable isotope labeling intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole-13C6Dissolving in organic solvent, adding dehydrating agent, and reacting with trifluoromethyl sulfinyl chloride to obtain stable isotope labeled compound formula 3 with structural formula shown below, wherein carbon atom on benzene ring is13C atom:
Figure BDA0001995525710000091
s4) dissolving the stable isotope labeled compound in the formula 3 for oxidation reaction to prepare the stable isotope labeled fipronil-13C6Or fipronil sulfone-13C6The structural formulas of the two are respectively shown as the following, wherein the carbon atom on the benzene ring is13C atom:
Figure BDA0001995525710000092
fipronil-13C6Fipronil sulfone-13C6
The synthetic route of the stable isotope labeled fipronil and the derivative thereof is as follows:
Figure BDA0001995525710000101
the invention relates to p-trifluoromethyl aniline-marked by stable isotope13C6The target compound with purity of more than 98 percent and isotopic abundance of more than 98 percent can be prepared by four-step simple synthesis. Fig. 1 is a GC-MS diagram of a stable isotope labeled compound of formula 3, in which the abscissa of fig. 1(a) and fig. 1(b) represents the peak-off time and mass-to-charge ratio, respectively, and it can be seen that 425.95 and 427.95 appear in the mass spectrum of the stable isotope labeled compound of formula 3, which are consistent with theoretical calculated values 419.93 and 421.93, and fragment ion peaks 356.95, 260.99, etc. appear at the same time, and are determined as fragment ions of the compound; FIG. 2 and FIG. 3 are the stable isotope labeled fipronil-13C6Liquid phase mass spectrum contrast diagram of non-labeled fipronil and stable isotope labeled fipronil sulfone-13C6The liquid mass spectrum contrast chart of the non-labeled fipronil sulfone, the abscissa is the mass-to-charge ratio, and the chart can see that the molecular weights of the fipronil sulfone are respectively increased by 6 after being labeled by the stable isotope, which proves that 6 carbon atoms are determined to be already labeled by the stable isotope13C atom substitution, and fipronil can be respectively obtained from the liquid phase mass spectrum13C6And fipronil sulfone-13C6The isotopic abundances of (a) are 98.9% and 99.0%, respectively. FIG. 4 and FIG. 5 are schematic diagrams of stable isotope-labeled fipronil-13C6Is/are as follows1HNMR spectra and13c NMR spectrum, solvent is deuterated methanol, horizontal coordinate is chemical shift, fipronil-13C6Hydrogen peak of (2) and13the peaks C all correspond to the structural formulas one to one. FIGS. 6 and 7 are stable isotope labeled fipronil sulfone-13C6Is/are as follows1H NMR spectrum and13c NMR spectrum, likewise, solvent deuterated methanol, abscissa chemical potentialMovable fipronil sulfone-13C6Hydrogen peak of (2) and13the C peaks are all in one-to-one correspondence with the structural formulas. FIG. 8 and FIG. 9 are the stable isotope labeled fipronil-13C6And stable isotope labeled fipronil sulfone-13C6The high performance liquid chromatogram of (1) is determined to have the purity of 98.3% and 99.7% respectively by adopting an area normalization method.
Example 1 Synthesis of 2, 6-dichloro-4-trifluoromethylaniline-13C6(Compound of formula 1)
Weighing 4.8g of NCS in a 250ml three-neck flask, adding 40ml of acetonitrile, stirring for dissolving, and dissolving 3g of p-trifluoromethylaniline in 30ml of acetonitrile by using a constant pressure dropping funnel13C6Slowly dropping into the reaction device, stirring for 3 hours at room temperature after dropping for half an hour. Most of the solvent was evaporated by rotary evaporation, ethyl acetate was added and dissolved with stirring, and the mixture was extracted with 50ml of pure water, and the organic phase was collected and dried over anhydrous sodium sulfate. Filtering, removing the solvent by rotary decompression to obtain the 2, 6-dichloro-4-trifluoromethylaniline-13C63.8g, 91% yield.
Example 2 preparation of 2, 6-dichloro-4-trifluoromethylaniline by oxidative chlorination13C6(Compound of formula 1)
In a 100ml reaction flask, 3g of p-trifluoromethylaniline-13C6Dissolving in 59g of hydrochloric acid (10%), heating to 50 ℃, slowly adding 13g of 30% hydrogen peroxide dropwise for oxidation chlorination reaction, and controlling the temperature to be kept between 50 and 60 ℃ for reaction for 2 hours. After the reaction is finished, standing and layering, taking the lower oil layer, washing with alkali and water, and then decompressing and rotatably removing the solvent to obtain the 2, 6-dichloro-4-trifluoromethylaniline-13C63.8g, 91% yield.
Example 3 preparation of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole-13C6(Compound of formula 2)
Adding 1.3g of sodium nitrite into a 250ml three-neck flask, dripping mixed acid (5 ml of concentrated sulfuric acid and 5ml of acetic acid) into an ice bath to obtain a thin paste, continuously stirring for 15min, and adding 2, 6-dichloro-4-trifluoromethylaniline-13C6Solution (3.8g in 8ml glacial acetic acid) was completed and continuedStirring for 15min, heating to 55 deg.C, and maintaining for 30 min. After cooling to below 10 deg.C, a solution of ethyl 2, 3-dicyanopropionate (3.0g in 5ml of glacial acetic acid) was added dropwise and stirring was continued for 15 min. Most of the acetic acid was distilled off under reduced pressure, 10ml of water was added, extraction was performed with methylene chloride, and the organic phase was collected.
The organic phase was neutralized with concentrated ammonia to PH 9.0 and stirred at room temperature for 3 hours to give a dark brown mixture. Standing, separating lower dichloromethane layer, extracting water layer with dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, and evaporating solvent to obtain brownish red viscous substance. After hot extraction with petroleum ether, the crystals rapidly crystallized upon standing at room temperature to give 4.9g of pale yellow crystals with a yield of 91.4%.
Example 4 preparation of 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6(Compound of formula 3).
In a 250ml three-necked flask, 4.9g of the compound of formula 2 are first dissolved in 100ml of toluene and 2ml of DMF, 5g of dried dimethylamine p-toluenesulfonate are added, 1.1g of phosphorus trichloride are then added and stirred at room temperature for 0.5h, 5g of freshly evaporated and dried trifluoromethanesulfonic chloride are then added dropwise, the temperature is raised to 90 ℃ and the stirring is carried out for 15 h. And (3) cooling to room temperature after the reaction is finished, adding 20ml of water, stirring for 0.5h, separating liquid, carrying out organic phase separation, and distilling to remove toluene to obtain a crude product of the compound I. Purification by column chromatography gave 5.4g of product in 81% yield.
Example 5 preparation of 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfonylimidazopyrazole-13C6(hereinafter referred to as fipronil-13C6)。
In a 100ml reaction flask, 1.8g of the compound of formula 3 was dissolved in 20ml of ethanol at room temperature, then 6g of trifluoroacetic acid and 35mg of boric acid were added, then 0.7g of 30% by mass hydrogen peroxide was added dropwise, and stirred at room temperature for 6 hours. Then the solvent is removed by rotation under reduced pressure to obtain fipronil-13C6The crude product is purified by a chromatographic column to obtain fipronil-13C61.56g, 81.7% yield.
Example 6 preparation of 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfonyl pyrazole-13C6(hereinafter referred to as fipronil sulfone-13C6)。
In a 100ml reaction flask, 1.8g of the compound of formula 3 was dissolved in 20ml of ethanol at room temperature, and then 3.3g of potassium hydrogen persulfate was added in mass fraction and stirred at 50 ℃ for 5 hours. Then the solvent is removed by rotation under reduced pressure to obtain fipronil sulfone-13C6The crude product is separated by column chromatography to obtain fipronil sulfone-13C61.93g, yield 95.2%.
Example 7 preparation of fipronil-13C6And fipronil sulfone-13C6
In a 100ml reaction flask, 1.8g of the compound of formula 3 was dissolved in 20ml of ethanol at room temperature, and then 1.2g of 70% m-chloroperoxybenzoic acid was added and stirred at 40 ℃ for 4 hours. After GC detects that the raw material is completely oxidized, the solvent is removed by rotation under reduced pressure to obtain fipronil-13C6Fipronil sulfone-13C6The mixture was separated by preparative column to obtain 1.2g fipronil-13C60.7g fipronil sulfone-13C6The total yield was 92.5%.

Claims (13)

1. Fipronil labeled by stable isotope13C6Or fipronil sulfone-13C6Characterized in that the fipronil-13C6The structural formula of (A) is as follows:
Figure FDA0001995525700000011
said fipronil sulfone-13C6The structural formula of (A) is as follows:
Figure FDA0001995525700000012
2. a stable isotope labeled fipronil derivative, which is characterized by the following structural formula:
Figure FDA0001995525700000021
3. a method for the synthesis of stable isotope labeled fipronil and its derivatives as claimed in claim 1 or 2, characterized by comprising the steps of:
s1) stable isotope labeling of p-trifluoromethylaniline-13C6Reacting with a chlorinating reagent to prepare the stable isotope labeled 2, 6-dichloro-4-trifluoromethylaniline-13C6；
S2) under the condition of mixed acidity, 2, 6-dichloro-4-trifluoromethylaniline-13C6Diazotizing, reacting with 2, 3-dicyano ethyl propionate to obtain the stable isotope labeling intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole-13C6；
S3) reacting 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole-13C6Dissolving in organic solvent, adding dehydrating agent, reacting with trifluoromethyl sulfinyl chloride to obtain 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethyl thiopyrazole-13C6；
S4) reacting 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6Dissolving and oxidizing to obtain the fipronil-containing material with stable isotope labeling13C6Or fipronil sulfone-13C6。
4. The method of synthesis according to claim 3, characterized in that: the chlorinating agent in the step S1) is N-bromosuccinimide, and the molar amount of the N-bromosuccinimide is p-trifluoromethylaniline-13C62-3 times of the reaction time, wherein the reaction temperature in the step S1) is controlled to be 20-30 ℃, and the reaction time is 2-4 hours.
5. The method of synthesis according to claim 3, characterized in that: the chlorinating agent in the step S1) is hydrochloric acid-hydrogen peroxide; the saltThe mass percentage concentration of the acid is 10-15 percent, and the mass amount of the acid is p-trifluoromethylaniline-13C617-21 times of; the mass percentage concentration of the hydrogen peroxide is 25-30 percent, and the mass dosage is p-trifluoromethylaniline-13C61.5-2.5 times of the reaction temperature in the step S1), and the reaction time is 2-3 hours at 50-60 ℃.
6. The method of synthesis according to claim 3, characterized in that: the step S2) is added with sodium nitrite to the 2, 6-dichloro-4-trifluoromethylaniline-13C6Diazotizing, wherein the mixed acid in the step S2) is concentrated sulfuric acid and glacial acetic acid which are mixed in equal volumes, the molar ratio of the concentrated sulfuric acid to the sodium nitrite is 4-5, and the sodium nitrite and 2, 6-dichloro-4-trifluoromethylaniline-13C6The molar ratio of the ethyl 2, 3-dicyanopropionate to the 2, 6-dichloro-4-trifluoromethylaniline-13C6The molar ratio is 1.5-2.
7. The method of synthesis according to claim 3, characterized in that: in the step S2), the initial reaction temperature is controlled to be 0-10 ℃, the reaction time is 15-30 minutes, and the subsequent reaction temperature is controlled to be 50-60 ℃, and the reaction time is 30-60 minutes.
8. The method of synthesis according to claim 3, characterized in that: the organic solvent in the step 3) is anhydrous and does not react with the trifluoromethyl sulfinyl chloride, and the organic solvent is one or a mixture of more of 1, 2-dichloroethane, toluene, chloroform and 1, 2-dichloroethane.
9. The method of synthesis according to claim 3, characterized in that: and in the step S3), the dehydrating agent is one or a mixture of more of phosphorus oxychloride, phosphorus trichloride and thionyl chloride.
10. The method of synthesis according to claim 3, characterized in that: the trifluoromethyl sulfinyl chloride and the intermediate 5-amino-3-cyano-1- (2) in the step 3)6-dichloro-4-trifluoromethyl) pyrazole-13C6The molar ratio of (A) to (B) is 1.1-1.5, the reaction temperature is 80-100 ℃, and the reaction time is 12-18 hours.
11. The method of synthesis according to claim 3, characterized in that: the oxidant in the step S4) is one or a mixture of more of m-chloroperoxybenzoic acid, hydrogen peroxide and potassium hydrogen persulfate.
12. The method of synthesis according to claim 3, characterized in that: the step S4) is performed by controlling the oxidizing agent and 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6The molar ratio of the target product is 1.3-1.5, and the obtained target product is sulfoxide fipronil-13C6(ii) a Control of oxidant and 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6The molar ratio is more than 10, and the obtained target product is fipronil sulfone-13C6Control the oxidant and the stable 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole-13C6The molar ratio of the target product is 1.5-10, and the obtained target product is fipronil-13C6With fipronil sulfone-13C6A mixture of (a).
13. The method of synthesis according to claim 3, characterized in that: the reaction temperature in the step S4) is 20-60 ℃, and the reaction time is 4-8 hours.
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CN102781920A (en) * 2010-03-03 2012-11-14 K·H·伽达 Process for synthesis of fipronil
CN106866426A (en) * 2017-02-27 2017-06-20 浙江巍华化工有限公司 A kind of method of comprehensive utilization of the trichlorobenzotrifluoride of accessory substance 2,4,5 for producing 3,4,5 trichlorobenzotrifluorides

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Publication number Priority date Publication date Assignee Title
EP0295117A1 (en) * 1987-06-12 1988-12-14 Rhone-Poulenc Agriculture Limited Derivatives of N-phenylpyrazoles
CN102781920A (en) * 2010-03-03 2012-11-14 K·H·伽达 Process for synthesis of fipronil
CN102633722A (en) * 2012-03-20 2012-08-15 金坛市凌云动物保健品有限公司 Fipronil preparation method
CN106866426A (en) * 2017-02-27 2017-06-20 浙江巍华化工有限公司 A kind of method of comprehensive utilization of the trichlorobenzotrifluoride of accessory substance 2,4,5 for producing 3,4,5 trichlorobenzotrifluorides

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