CN111689899B - Stable isotope labeled fipronil and derivative thereof and synthetic preparation method - Google Patents
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Abstract
The invention discloses three novel compounds: stable isotope labeled fipronil and its 2 derivatives, and their synthesis and preparation method. The synthesizing method uses stable isotope labeled para-trifluoromethyl aniline- 13 C 6 Is used as a raw material, and one of the derivatives is obtained through three steps of chemical reactions: 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 The method comprises the steps of carrying out a first treatment on the surface of the Then the derivative is subjected to one-step oxidation reaction to obtain the fipronil with stable isotope labeling 13 C 6 And another derivative thereof: stable isotope labeled fipronil sulfone- 13 C 6 . The 3 compounds are synthesized and prepared for the first time, and the chemical purity and the isotope abundance of the compounds reach more than 98 percent, thus the compounds are very innovative; and the method can be used as an internal standard for developing a stable isotope internal standard method, and has potential market economic value.
Description
Technical Field
The invention relates to a stable isotope labeled compound and a synthesis preparation method thereof, in particular to stable isotope labeled fipronil and derivatives thereof and a synthesis preparation method thereof.
Background
Fipronil and its derivatives belong to phenylpyrazole compounds, and are high-efficiency pesticides developed first by the company of Rona-Planck, france. It is not only broad in insecticidal spectrum but also harmless to crops, so it has been widely used in agriculture and horticulture, and is recommended by many pesticide specialists as one of the preferred varieties to replace high-toxic organophosphorus pesticides. However, as researchers further research, fipronil is found to be extremely unfriendly to the environment and can influence butterflies, dragonflies and the like around crops, so that fipronil is forbidden in 10 months 1 in 2009 in China. The european union law also prescribes that fipronil is prohibited from being directly consumed by domestic animals, and is not applicable to livestock in the human food industry chain. World health organization indicates that eating food containing fipronil at high concentration can damage liver, thyroid and kidneys. Therefore, the detection and supervision of the residues of the medicines in foods 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 have the defects of low sensitivity, complicated method, only semi-quantitative analysis and the like. The newly developed stable isotope dilution mass spectrometry (Isotope Dilution Mass Spectrometry, IDMS) adopts a stable isotope labeled compound with the same molecular structure as the detected substance as an internal standard substance, and uses a high-resolution liquid chromatography-mass spectrometer (LC-MS) to detect the compound, and the ratio of ions with corresponding mass numbers is measured by the mass spectrometer and compared with the standard ratio to achieve the purpose of accurate quantification. The isotope internal standard is adopted, so that not only can the deviation caused by a sample in a pretreatment step be effectively reduced, but also the error brought by an instrument can be eliminated. The combination of the characteristic of stable isotope internal standard with the high sensitivity of LC-MS and the ability to process complex samples has led to the acceptance of chromatographic-isotope dilution mass spectrometry technology as a benchmark quantification method for the measurement of trace and trace organics with increasing application.
At present, few synthesis studies on stable isotope labeled fipronil and derivatives are carried out, and no commercial products exist. Therefore, no corresponding detection method using stable isotope labeled fipronil and derivatives as internal standard exists.
Disclosure of Invention
The invention aims to provide stable isotope labeled fipronil and derivatives thereof as well as 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 aim of the invention can be achieved by the following technical scheme:
fipronil with stable isotope labeling 13 C 6 Or fipronil sulfone- 13 C 6 Wherein the fipronil is 13 C 6 The structural formula is as follows:
the fipronil sulfone 13 C 6 The structural formula is as follows:
a stable isotope labeled fipronil derivative, wherein the structural formula is as follows:
a synthetic preparation method of stable isotope labeled fipronil and derivatives thereof comprises the following steps: s1) labeling stable isotope of para-trifluoromethylaniline 13 C 6 And chloridizing reagent to obtain stable isotope labeled 2, 6-dichloro-4-trifluoromethyl aniline 13 C 6 The method comprises the steps of carrying out a first treatment on the surface of the S2) under the condition of mixed acidity, 2, 6-dichloro-4-trifluoromethyl aniline- 13 C 6 After diazotization, withEthyl 2, 3-dicyanopropionate to obtain stable isotope labeled intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 The method comprises the steps of carrying out a first treatment on the surface of the S3) 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 Dissolving in organic solvent, adding dehydrating agent, and reacting with trifluoromethyl sulfinyl chloride to obtain 5-amino-1- (2, 6-dichloro-4-trifluoromethyl phenyl) -3-cyano-4-trifluoromethyl thiopyrazole- 13 C 6 The method comprises the steps of carrying out a first treatment on the surface of the S4) 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 Dissolving and oxidizing to obtain the stable isotope labeled fipronil 13 C 6 Or fipronil sulfone- 13 C 6 。
Further: the chlorinating reagent in the step S1) is N-bromosuccinimide, and the molar dosage of the N-bromosuccinimide is p-trifluoromethylaniline- 13 C 6 2-3 times of the reaction temperature is controlled to be 20-30 ℃ in the step S1), and the reaction time is 2-4 hours.
Further: the chlorinating reagent in the step S1) is hydrochloric acid-hydrogen peroxide; the mass percentage concentration of the hydrochloric acid is 10-15%, and the mass dosage of the hydrochloric acid is p-trifluoromethyl aniline- 13 C 6 17-21 times of (2); the mass percentage concentration of the hydrogen peroxide is 25-30%, and the mass dosage of the hydrogen peroxide is p-trifluoromethyl aniline- 13 C 6 1.5-2.5 times, wherein the reaction temperature in the step S1) is 50-60 ℃ and the reaction time is 2-3 hours.
Further: sodium nitrite is added in the step S2) to 2, 6-dichloro-4-trifluoromethyl aniline- 13 C 6 Diazotizing, wherein the mixed acid in the step S2) is mixed concentrated sulfuric acid and glacial acetic acid in equal volume, the molar ratio of the concentrated sulfuric acid to sodium nitrite is 4-5, and the molar ratio of the sodium nitrite to the 2, 6-dichloro-4-trifluoromethylaniline is that 13 C 6 The molar ratio of the ethyl dicyanopropionate to the 2, 6-dichloro-4-trifluoromethylaniline is 1.1-1.5,2,3 13 C 6 The 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 controlled to be 15-30 minutes, the subsequent reaction temperature is controlled to be 50-60 ℃, and the reaction time is controlled to be 30-60 minutes.
Further: the organic solvent in the step 3) is anhydrous and does not react with trifluoromethyl sulfinyl chloride, and the organic solvent is one or a mixture of more than one of 1, 2-dichloroethane, toluene, chloroform and 1, 2-dichloroethane.
Further: the dehydrating agent in the step S3) is one or a mixture of more of phosphorus oxychloride, phosphorus trichloride and thionyl chloride.
Further: the trifluoromethyl sulfinyl chloride in the step 3) and an intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 The molar ratio of (2) 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 hydrogen persulfate.
Further: the step S4) is performed by controlling the oxidant and the 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 The molar ratio of the sulfoxaflor to the fluorine-containing compound is 1.3 to 1.5, and the obtained target product is sulfoxaflor- 13 C 6 The method comprises the steps of carrying out a first treatment on the surface of the Controlling the oxidation agent and 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 The molar ratio of the fluorine to the fluorine is more than 10, and the obtained target product is fipronil sulfone- 13 C 6 Controlling the oxidation agent and stabilizing 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 The molar ratio of the fipronil to the chlorfenapyr is 1.5-10, and the obtained target product is fipronil 13 C 6 With fipronil sulfone- 13 C 6 Is a mixture of (a) and (b).
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 invention provides 3 novel stable isotope labeled compounds and a synthesis method thereof. Marked by stable isotopes2, 6-dichloro-4-trifluoromethylaniline- 13 C 6 One of the derivatives is obtained by three steps of reaction synthesis as a raw material: stable isotope labeled 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 (Compound of formula 3), and then oxidizing the compound of formula 3 to obtain fipronil 13 C 6 And another derivative: fipronil sulfone- 13 C 6 The isotope atoms cannot fall off in each reaction process, so that the stable isotope atoms have high utilization rate; the invention has simple synthesis process, and the product is easy to separate and purify, and the chemical purity and the isotope abundance of the obtained product reach more than 98 percent. The 3 compounds are synthesized and prepared for the first time, and have great innovation; and the method 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 diagram of a compound of formula 3 according to the invention;
FIG. 2 shows the stable isotope labeled fipronil obtained in the present invention 13 C 6 A liquid phase mass spectrum contrast diagram of the non-labeled fipronil;
FIG. 3 shows the stable isotope labeled fipronil sulfone- 13 C 6 A liquid mass spectrum contrast diagram of the non-labeled fipronil sulfone;
FIG. 4 shows the stable isotope labeled fipronil obtained in the present invention 13 C 6 A kind of electronic device 1 H NMR spectrum;
FIG. 5 shows the stable isotope labeled fipronil obtained in the present invention 13 C 6 A kind of electronic device 13 C NMR spectrum;
FIG. 6 shows the stable isotope labeled fipronil sulfone- 13 C 6 A kind of electronic device 1 H NMR spectrum;
FIG. 7 shows the stable isotope labeled fipronil sulfone- 13 C 6 A kind of electronic device 13 C NMR spectrum;
FIG. 8 shows the stable isotope labeled fipronil obtained in the present invention 13 C 6 Is a high performance liquid chromatogram of (2);
FIG. 9 shows the stable isotope labeled fipronil sulfone- 13 C 6 Is a high performance liquid chromatogram of (2).
Detailed Description
The invention is further described below with reference to the drawings and examples of implementation.
The invention relates to three new stable isotope labeled compounds and a synthesis preparation method thereof. 3. The novel stable isotope labeled compounds are respectively: 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 (hereinafter referred to as Compound formula 3), 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfinyl pyrazole- 13 C 6 (hereinafter abbreviated as fipronil- 13 C 6 ) And 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfonylpyrazole- 13 C 6 (hereinafter abbreviated as fipronil sulfone- 13 C 6 ). The structural formula of the three compounds is shown in the specification, wherein carbon atoms on benzene rings are 13 C atom:
s1) labeling stable isotope of para-trifluoromethylaniline 13 C 6 And chloridizing reagent to obtain stable isotope labeled 2, 6-dichloro-4-trifluoromethyl aniline 13 C 6 The structural formula is shown in formula 1, wherein the carbon atom on the benzene ring is 13 C atom:
s2) under mixed acidic conditions, the stable isotope labeled 2, 6-dichloro-4-trifluoromethylaniline- 13 C 6 Diazotizing, and reacting with 2, 3-dicyanopropionic acid to obtain stable isotope labeled intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 The structural formula is shown in formula 2, wherein the carbon atom on the benzene ring is 13 C atom:
s3) 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole, an intermediate for labeling the stable isotopes 13 C 6 Dissolving in organic solvent, adding dehydrating agent, and reacting with trifluoromethyl sulfinyl chloride to obtain stable isotope labeled compound formula 3 with the following structural formula, wherein carbon atom on benzene ring is 13 C atom:
s4) dissolving the stable isotope labeled compound formula 3 and carrying out oxidation reaction to obtain the stable isotope labeled fipronil 13 C 6 Or fipronil sulfone- 13 C 6 The structural formulas of the two are respectively shown as the following, wherein the carbon atom on the benzene ring is 13 C atom:
fipronil-containing material 13 C 6 Fipronil sulfone- 13 C 6
The synthetic route of the stable isotope labeled fipronil and the derivatives thereof is as follows:
the invention uses stable isotope labeled p-trifluoromethyl aniline- 13 C 6 The raw materials are synthesized by four steps of simple operation, the purity is more than 98 percent,the target compound with the isotope abundance of more than 98 percent. FIG. 1 is a GC-MS diagram of a stable isotope labeled compound of formula 3, wherein the abscissas of FIG. 1 (a) and FIG. 1 (b) are peak time and mass-to-charge ratio, respectively, and as can be seen from the diagram, peaks 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 such as 356.95 and 260.99 appear at the same time, and are determined as fragment ions of the compound; FIGS. 2 and 3 show stable isotope labeled fipronil respectively 13 C 6 Liquid mass spectrum contrast diagram of non-labeled fipronil and stable isotope labeled fipronil sulfone- 13 C 6 Comparing the liquid phase mass spectrum of the non-marked fipronil sulfone with the mass-to-charge ratio on the abscissa, the molecular weight of the fipronil sulfone is respectively increased by 6 after being marked by stable isotopes, which proves that 6 carbon atoms are confirmed to be marked 13 C atom substitution, and fipronil can be obtained from liquid phase mass spectrum 13 C 6 And fipronil sulfone- 13 C 6 The isotopic abundance of (c) is 98.9% and 99.0%, respectively. FIGS. 4 and 5 are, respectively, stabilized isotopologue labeled fipronil- 13 C 6 A kind of electronic device 1 H NMR spectra 13 C NMR spectra, deuterated methanol as solvent, chemical shift on the abscissa, fipronil-based material from both spectra 13 C 6 Hydrogen peak sum of (2) 13 The C peak corresponds to the structural formula one by one. FIGS. 6 and 7 are respectively stable isotope labeled fipronil sulfone- 13 C 6 A kind of electronic device 1 H NMR spectra 13 C NMR spectrum, likewise, deuterated methanol as solvent, chemical shift on the abscissa, fipronil sulfone- 13 C 6 Hydrogen peak sum of (2) 13 The C peak is also in one-to-one correspondence with the structural formula. FIGS. 8 and 9 are respectively stable isotope labeled fipronil- 13 C 6 And stable isotope labeled fipronil sulfone- 13 C 6 The high performance liquid chromatogram of (2) adopts an area normalization method to determine that the purity is 98.3 percent and 99.7 percent respectively.
EXAMPLE 1 Synthesis of 2, 6-dichloro-4-trifluoromethylaniline Using electrophilic substitution reagent NCS 13 C 6 (Compound of formula 1)
NCS 4.8g was weighed into a 250ml three-necked flask, 40ml of acetonitrile was added, and the mixture was stirred and dissolved, and 3g of p-trifluoromethylaniline (3 g/ml) dissolved in 30ml of acetonitrile was introduced into the flask with a constant pressure dropping funnel 13 C 6 Slowly dripping into the reaction device, and stirring at room temperature for 3 hours after half an hour of dripping. Most of the solvent was distilled off by rotary evaporation, ethyl acetate was added thereto and stirred for dissolution, extraction was performed with 50ml of pure water, and the organic phase was collected and dried over anhydrous sodium sulfate. Filtering, and then decompressing and spin-removing the solvent to obtain the 2, 6-dichloro-4-trifluoromethyl aniline 13 C 6 3.8g, 91% yield.
EXAMPLE 2 preparation of 2, 6-dichloro-4-trifluoromethylaniline by oxidative Chlorination 13 C 6 (Compound of formula 1)
In a 100ml reaction flask, 3g of p-trifluoromethylaniline- 13 C 6 Dissolving in 59g hydrochloric acid (10%), heating to 50deg.C, slowly adding 13g 30% hydrogen peroxide dropwise for oxidation chlorination reaction, maintaining the temperature at 50-60deg.C, and reacting for 2 hr. After the reaction is finished, standing and layering, taking out a lower oil layer, and carrying out reduced pressure spin-removing solvent after alkali washing and water washing to obtain 2, 6-dichloro-4-trifluoromethyl aniline- 13 C 6 3.8g, 91% yield.
EXAMPLE 3 preparation of 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 (Compound of formula 2)
Adding 1.3g of sodium nitrite into 250ml of a three-necked flask, dropwise adding mixed acid (concentrated sulfuric acid 5ml, acetic acid 5 ml) into an ice bath to obtain a thin paste, continuously stirring for 15min, and adding 2, 6-dichloro-4-trifluoromethylaniline 13 C 6 The solution (3.8 g in 8ml glacial acetic acid) was stirred for a further 15min after which the temperature was raised to 55℃and maintained for 30min. Cooled below 10 ℃, added dropwise with ethyl 2, 3-dicyanopropionate solution (3.0 g dissolved in 5ml glacial acetic acid) and stirred for 15min. Most of the acetic acid was distilled off under reduced pressure, 10ml of water was added, and the mixture was extracted with methylene chloride to collect an organic phase.
The organic phase was neutralized to ph=9.0 with concentrated aqueous ammonia and stirred at room temperature for 3 hours to give a dark brown mixture. Standing, separating out dichloromethane at the lower layer, extracting aqueous layer with dichloromethane, mixing organic layers, drying with anhydrous sodium sulfate, and evaporating solvent to obtain brownish red viscous substance. After petroleum ether thermal extraction, the mixture was allowed to stand at room temperature to rapidly crystallize, thereby obtaining 4.9g of pale yellow crystals, and the yield was 91.4%.
EXAMPLE 4 preparation of 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 (Compound of formula 3).
In a 250ml three-necked flask, 4.9g of the compound of formula 2 was dissolved in 100ml of toluene and 2ml of DMF, 5g of dried dimethylamine p-toluenesulfonate salt was added, 1.1g of phosphorus trichloride was then added, stirring was carried out at room temperature for 0.5h, then 5g of newly distilled trifluoromethylsulfinyl chloride was added dropwise, and the temperature was raised to 90℃and stirring was carried out for 15 h. After the reaction is completed, cooling to room temperature, adding 20ml of water, stirring for 0.5h, separating liquid, organic phase, distilling to remove toluene, and obtaining a crude product of the compound I. Purification by column chromatography gave 5.4g of the product in 81% yield.
EXAMPLE 5 preparation of 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfinyl pyrazole- 13 C 6 (hereinafter abbreviated as fipronil) 13 C 6 )。
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 stirring was carried out at room temperature for 6 hours. Then the solvent is removed by decompression and spin-drying to obtain fipronil 13 C 6 Purifying the crude product by a chromatographic column to obtain fipronil 13 C 6 1.56g, 81.7% yield.
EXAMPLE 6 preparation of 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfonylpyrazole- 13 C 6 (hereinafter abbreviated as fipronil sulfone- 13 C 6 )。
In a 100ml reaction flask, 1.8g of the compound of formula 3 was dissolved in 20ml of ethanol at room temperature, followed by addition of 3.3g of potassium hydrogen persulfate in mass fraction and stirring at 50℃for 5 hours. Then the solvent is removed by decompression and spin-drying to obtain fipronil sulfone- 13 C 6 Separating the crude product by column chromatography to obtain fipronil sulfone- 13 C 6 1.93g, yield 95.2%.
EXAMPLE 7 preparation of fipronil 13 C 6 And fipronil sulfone- 13 C 6
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 thereto and stirred at 40℃for 4 hours. After the raw material is completely oxidized by GC, the solvent is removed by decompression spin to obtain fipronil 13 C 6 Fipronil sulfone- 13 C 6 The mixture is separated by a preparation column to obtain 1.2g fipronil- 13 C 6 0.7g fipronil sulfone- 13 C 6 The total yield was 92.5%.
Claims (12)
1. Fipronil with stable isotope labeling 13 C 6 Or fipronil sulfone- 13 C 6 Characterized in that the fipronil is 13 C 6 The structural formula is as follows:
the fipronil sulfone 13 C 6 The structural formula is as follows:
the synthesis method comprises the following steps:
s1) labeling stable isotope of para-trifluoromethylaniline 13 C 6 And chloridizing reagent to obtain stable isotope labeled 2, 6-dichloro-4-trifluoromethyl aniline 13 C 6 ；
S2) under the condition of mixed acidity, 2, 6-dichloro-4-trifluoromethyl aniline- 13 C 6 Diazotizing and reacting with 2, 3-dicyanopropionic acid ethyl ester to obtain stable isotope labeling intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 ；
S3) 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 Dissolving in organic solvent, adding dehydrating agent, and mixing with trifluoromethylAfter reaction of the sulfoxyl chloride, 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole was obtained 13 C 6 ；
S4) 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 Dissolving and oxidizing to obtain the stable isotope labeled fipronil 13 C 6 Or fipronil sulfone- 13 C 6 。
2. The synthesis method of the stable isotope labeled fipronil derivative is characterized by comprising the following structural formula:
the synthesis method comprises the following steps:
s1) labeling stable isotope of para-trifluoromethylaniline 13 C 6 And chloridizing reagent to obtain stable isotope labeled 2, 6-dichloro-4-trifluoromethyl aniline 13 C 6 ；
S2) under the condition of mixed acidity, 2, 6-dichloro-4-trifluoromethyl aniline- 13 C 6 Diazotizing and reacting with 2, 3-dicyanopropionic acid ethyl ester to obtain stable isotope labeling intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 ；
S3) 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 Dissolving in organic solvent, adding dehydrating agent, and reacting with trifluoromethyl sulfinyl chloride to obtain 5-amino-1- (2, 6-dichloro-4-trifluoromethyl phenyl) -3-cyano-4-trifluoromethyl thiopyrazole- 13 C 6 。
3. The synthesis method according to claim 1 or 2, characterized in that: the chlorinating reagent in the step S1) is N-bromosuccinimide, and the molar amount of the N-bromosuccinimide is p-trifluoromethylAniline-containing material 13 C 6 2-3 times of the reaction temperature is controlled to be 20-30 ℃ in the step S1), and the reaction time is 2-4 hours.
4. The synthesis method according to claim 1 or 2, characterized in that: the chlorinating reagent in the step S1) is hydrochloric acid-hydrogen peroxide; the mass percentage concentration of the hydrochloric acid is 10-15%, and the mass dosage of the hydrochloric acid is p-trifluoromethyl aniline- 13 C 6 17-21 times of (2); the mass percentage concentration of the hydrogen peroxide is 25-30%, and the mass dosage of the hydrogen peroxide is p-trifluoromethyl aniline- 13 C 6 1.5-2.5 times, wherein the reaction temperature in the step S1) is 50-60 ℃ and the reaction time is 2-3 hours.
5. The synthesis method according to claim 1 or 2, characterized in that: sodium nitrite is added in the step S2) to prepare the 2, 6-dichloro-4-trifluoromethyl aniline 13 C 6 Diazotizing, wherein the mixed acid in the step S2) is mixed concentrated sulfuric acid and glacial acetic acid in equal volume, the molar ratio of the concentrated sulfuric acid to sodium nitrite is 4-5, and the molar ratio of the sodium nitrite to the 2, 6-dichloro-4-trifluoromethylaniline is that 13 C 6 The molar ratio of the ethyl dicyanopropionate to the 2, 6-dichloro-4-trifluoromethylaniline is 1.1-1.5,2,3 13 C 6 The molar ratio is 1.5-2.
6. The synthesis method according to claim 1 or 2, characterized in that: in the step S2), the initial reaction temperature is controlled to be 0-10 ℃, the reaction time is controlled to be 15-30 minutes, the subsequent reaction temperature is controlled to be 50-60 ℃, and the reaction time is controlled to be 30-60 minutes.
7. The synthesis method according to claim 1 or 2, characterized in that: the organic solvent in the step 3) is anhydrous and does not react with trifluoromethyl sulfinyl chloride, and the organic solvent is one or a mixture of more than one of 1, 2-dichloroethane, toluene, chloroform and 1, 2-dichloroethane.
8. The synthesis method according to claim 1 or 2, characterized in that: the dehydrating agent in the step S3) is one or a mixture of more of phosphorus oxychloride, phosphorus trichloride and thionyl chloride.
9. The synthesis method according to claim 1 or 2, characterized in that: the trifluoromethyl sulfinyl chloride in the step 3) and an intermediate 5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethyl) pyrazole- 13 C 6 The molar ratio of (2) is 1.1-1.5, the reaction temperature is 80-100 ℃, and the reaction time is 12-18 hours.
10. The synthesis method according to claim 1, wherein: the oxidant in the step S4) is one or a mixture of more of m-chloroperoxybenzoic acid, hydrogen peroxide and potassium hydrogen persulfate.
11. The synthesis method according to claim 1, wherein: the step S4) is performed by controlling the oxidant and the 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 The molar ratio of the sulfoxaflor to the chlorfenapyr is 1.3-1.5, and the obtained target product is sulfoxaflor- 13 C 6 The method comprises the steps of carrying out a first treatment on the surface of the Controlling the oxidation agent and 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 The molar ratio of the fluorine to the fluorine is more than 10, and the obtained target product is fipronil sulfone- 13 C 6 Controlling the oxidation agent and stabilizing 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylthiopyrazole- 13 C 6 The molar ratio of the fipronil to the chlorfenapyr is 1.5-10, and the obtained target product is fipronil 13 C 6 With fipronil sulfone- 13 C 6 Is a mixture of (a) and (b).
12. The synthesis method according to claim 1, wherein: the reaction temperature in the step S4) is 20-60 ℃ and the reaction time is 4-8 hours.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0295117A1 (en) * | 1987-06-12 | 1988-12-14 | Rhone-Poulenc Agriculture Limited | Derivatives of N-phenylpyrazoles |
| 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 |
| 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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| STN检索报告;王沙沙;《STN检索报告》;20221206;第14页 * |
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