CN114573494A - Preparation method of chlorfenapyr - Google Patents

Preparation method of chlorfenapyr Download PDF

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CN114573494A
CN114573494A CN202210389911.2A CN202210389911A CN114573494A CN 114573494 A CN114573494 A CN 114573494A CN 202210389911 A CN202210389911 A CN 202210389911A CN 114573494 A CN114573494 A CN 114573494A
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reaction
chlorophenyl
trifluoromethylpyrrole
chlorfenapyr
tetrahydrofuran
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CN114573494B (en
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刘新乐
王建昌
王锡峰
薛宏斌
罗瑞生
王振江
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Shandong Weifang Shuangxing Pesticide Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention relates to a method for preparing chlorfenapyr. In a mixed solvent, under the existence of a catalyst and an acid-binding agent, carrying out bromination reaction on 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile and bromine to prepare an intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile; and reacting the intermediate with chlorobromomethane and sodium ethoxide respectively under the action of alkali, and performing post-treatment to obtain a target product, namely the chlorfenapyr. The method has the advantages of simple reaction steps, mild reaction conditions, and great improvement in both yield and purity of the reaction, and has good industrial application value.

Description

Preparation method of chlorfenapyr
Technical Field
The invention relates to a preparation method of chlorfenapyr.
Background
Chlorfenapyr (chlorofenapyr), trade name: except, chemical name: 4-bromo-2- (4-chlorphenyl) -1-ethoxymethyl-5- (trifluoromethyl) pyrrole-3-nitrile (m.p. 100-101 ℃) is a novel phenylpyrrole insecticide and acaricide, and the action point of the novel phenylpyrrole insecticide and acaricide is mitochondria in insect cells, which is different from the currently commonly used insecticides. The product has the advantages of broad insecticidal spectrum, high activity, long persistent period, safety to beneficial organisms, environmental friendliness, etc., and has contact poisoning and stomach poisoning effects.
The method for synthesizing the chlorfenapyr is more, wherein 2-p-chlorophenyl-5-trifluoromethyl-3-cyanopyrrole is a key intermediate for synthesizing the chlorfenapyr, and the intermediate is subjected to bromination reaction and substitution reaction with chloromethyl ethyl ether to prepare the chlorfenapyr. However, since the pyrrole ring of the 2-p-chlorophenyl-5-trifluoromethyl-3-cyanopyrrole contains chlorophenyl, trifluoromethyl and cyano, all of which are electron-withdrawing groups, the activity of the intermediate during bromination reaction is low, and the product and purity are not high.
Basf corporation (CN 110382462 a) found that when bromination is carried out, DIPEA is used as an acid-binding agent instead of triethylamine, and the yield of bromination can be improved. Meanwhile, the post-treatment is simpler and more convenient, and the alkali DIPEA is easy to recover. The yield of the bromination step of a3 in the example of said patent was 88.2%. Comparative example B3 the yield of the bromination step was only 75.3% when triethylamine was used as the base.
When the Biqing et al (except for the synthetic research and the process improvement, the Master's academic thesis of Zhejiang university) synthesizes 4-bromo-2- (4-chlorophenyl) -5-trifluoromethylpyrrole-3-nitrile, the bromination reaction is carried out in the presence of a catalyst M by taking 2- (4-chlorophenyl) -5-trifluoromethylpyrrole-3-nitrile as a raw material, a mixed solvent of chloroform and DMF and liquid bromine as a bromination reagent, and the purity of the product is up to 93.6 percent, and the yield is up to 99 percent. Generating waste water containing more than 15 percent of HBr, and recovering bromine by chlorine gas oxidation. Although the yield of the reaction is high, the specific composition of the M is not disclosed and the product purity is not high.
Adding 2- (4-chlorphenyl) -5-trifluoromethyl pyrrole-3-nitrile and an oxidant into a polar solvent for nymph and the like (CN 102746208A), uniformly mixing, adding bromine, and after the reaction is finished, carrying out post-treatment to obtain 4-bromo-2- (4-chlorphenyl) -5-trifluoromethyl pyrrole-3-nitrile with the yield of 92-96%.
Liu source and the like (CN 109369498A) disclose that 2-p-chlorophenyl-5-trifluoromethyl pyrrole-3-nitrile solution and bromine solution are continuously introduced into a microreactor simultaneously for reaction, the obtained mixed solution flows through more than two reaction modules in the microreactor and then reacts with hydrogen peroxide solution introduced into the microreactor, and distillation is carried out to obtain 4-bromo-2-p-chlorophenyl-5-trifluoromethyl pyrrole-3-nitrile.
Xushangcheng et al (Nanjing university of agriculture, journal 2004, 27 (2): 105-108) disclose that a bromination reaction is carried out between 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile solution and bromine with a yield of 91.6% by using sodium bicarbonate as an acid-binding agent.
Luyang et al (modern pesticides, 2007, 6 (2): 22-25 and 28) disclose that 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile undergoes a substitution reaction with bromine in chlorobenzene to obtain 2-p-chlorophenyl-4-bromo-5- (trifluoromethyl) pyrrole-3-carbonitrile, and an acid-binding agent is not required to be added during the reaction, with a yield of 90.7%.
In the process of preparing chlorfenapyr in the prior art, a great deal of research is carried out for improving the yield and the purity of bromination reaction, but the yield and the purity of the obtained product still need to be improved, and the production cost needs to be reduced. Therefore, the development of a new method for preparing the chlorfenapyr still has huge market prospect and social benefit.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the preparation method of the chlorfenapyr is high in product purity, high in yield, mild in reaction condition and simple in post-treatment.
In order to solve the technical problem, the invention provides a method for preparing chlorfenapyr, which comprises the following steps:
1) in a mixed solvent, under the existence of a catalyst and an acid-binding agent, carrying out bromination reaction on 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile and bromine to prepare an intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile;
2) respectively reacting 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile with chlorobromomethane and sodium ethoxide under the action of alkali, and performing post-treatment to obtain a target product, namely chlorfenapyr;
the specific reaction formula is as follows:
Figure BDA0003596371520000031
preferably, the mixed solvent in step 1) is a mixed solvent of tetrahydrofuran and another inert solvent.
Suitable inert solvents are aliphatic hydrocarbons, preferably aliphatic C5-C16Hydrocarbons, more preferably C5-C16Alkanes, or C5-C16Cycloalkanes such as pentane, hexane, cyclohexane or petroleum ether; halogenated hydrocarbons, preferably halogenated aliphatic C1-C6Alkanes, or halogenated aromatic C6-C10Hydrocarbons, e.g. CH2Cl2、CHCl3、CCl4、CH2ClCH2Cl、CCl3CH3、CHCl2CH2Cl、CCl2CCl2Or chlorobenzene; ethers, preferably C1-C6Cycloalkyl ether, C1-C6alkyl-C1-C6Alkyl ethers, C1-C6alkyl-C3-C6Cycloalkyl ether, C1-C6polyol-C1-C6Alkyl ethers and C1-C6alkyl-C6-C10Aryl ethers, e.g. CH3CH2OCH2CH3、(CH3)2CHOCH(CH3)2、CH3OC(CH3)3(MTBE)、CH3OCH3(DME)、CH3OCH2CH2OCH3、CH3OC(CH3)2CH2CH3And diethylene glycol; esters, preferably aliphatic C1-C6Alcohols with aliphatic C1-C6Esters of carboxylic acids, aromatic C6-C10Alcohols with aromatic C6-C10Esters of carboxylic acids, omega-hydroxy-C1-C6Cyclic esters of carboxylic acids, e.g. CH3C (O) OCH2CH3、CH3C(O)OCH3、CH3C(O)OCH2CH2CH2CH3、CH3C(O)OCH(CH3)CH2CH3、CH3C(O)OC(CH3)、CH3CH2CH2C(O)OCH2CH3、CH3CH(OH)C(O)OCH2CH3、CH3CH(OH)C(O)OCH3、CH3C(O)OCH2CH(CH3)2、CH3C(O)OCH(CH3)2、CH3CH2C(O)OCH3Benzyl benzoate and gamma-butyrolactone; carbonates, e.g. ethylene carbonate, propylene carbonate, CH3CH2OC(O)OCH2CH3And CH3OC(O)OCH3(ii) a Nitriles, preferably C1-C6Nitriles, e.g. ACN and CH3CH2CN; alcohols, preferably C1-C4Alcohols and C2-C4Alkanediols, e.g. CH3OH、CH3CH2OH、CH3CH2CH2OH、CH3CH(OH)CH3、CH3(CH2)3OH and C (CH)3)3OH、CH2(OH)CH2(OH)、CH3CH(OH)CH2OH; amide and urea derivatives, preferably DMF, NMP, DMA, DMI, DMPU, HMPA; in addition, DMSO and sulfolane.
More preferably, the mixture solvent in the step 1) is a mixture solvent of tetrahydrofuran and carbon tetrachloride; most preferably, in the mixed solvent, the volume ratio of tetrahydrofuran to carbon tetrachloride is 5: 1-2.
Preferably, the catalyst in step 1) is iron powder, manganese dioxide or iron tribromide; more preferably iron powder.
Preferably, the acid-binding agent in the step 1) is selected from 4-dimethylaminopyridine, DIPEA, triethylamine, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; most preferably, the acid scavenger is selected from 4-dimethylaminopyridine.
Preferably, the molar ratio of the 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile, the bromine, the catalyst and the acid-binding agent in the step 1) is 1:1.0-2.0:0.1-0.2:1.0-3.0, and more preferably, the molar ratio is 1:1.0-1.2:0.1-0.15: 1.0-1.5.
Preferably, the reaction temperature of step 1) is 30-60 ℃, more preferably 40-50 ℃;
preferably, the reaction time of step 1) is 2 to 10 hours, more preferably 3 to 5 hours.
The reaction mixture of step 1) can be worked up in a conventional manner, for example by mixing with water, separating the phases and, if appropriate, purifying the crude product in a conventional manner. The solvent is generally removed from the reaction mixture by distillation after the reaction of step 1) is complete. Alternatively, it is also possible to add water to the mixture after the reaction is complete, to remove part of the solvent by distillation, to remove the aqueous layer and to dry the organic layer containing the compound of formula III, for example by adding hygroscopic material. The product of step 1) can also be obtained by crystallization from the organic layer or by removal of the organic solvent.
Preferably, the post-treatment method of step 1) is as follows: and cooling the reaction liquid, adding water, stirring, distilling to remove the mixed solvent, separating out a large amount of light yellow solid in the water phase, filtering, washing the filter cake with water for three times, collecting the filter cake, and drying to obtain the intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile.
The reaction process of step 2) can be carried out in a manner common in the art.
Preferably, the reaction process of step 2) is: dissolving 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile in tetrahydrofuran, slowly dropwise adding tetrahydrofuran containing sodium hydride, stirring for reaction, dropwise adding bromochloromethane, continuing to react, treating with tetrahydrofuran solution containing sodium ethoxide, reacting for a period of time, detecting the reaction process by TLC, cooling, filtering after the reaction is finished, removing the solvent, and recrystallizing with n-hexane/ethyl acetate mixed solvent to obtain white solid chlorfenapyr.
The pyrrole ring of the 2-p-chlorophenyl-5-trifluoromethyl-3-cyanopyrrole contains chlorphenyl, trifluoromethyl and cyano, and all the groups are electron-withdrawing groups, so that the activity of the intermediate in bromination reaction is low. The method of the invention can effectively reduce the activation energy of the bromination reaction by introducing the catalyst in the bromination step, thereby promoting the reaction and improving the reaction yield.
In addition, because hydrobromic acid is generated in the bromination reaction, an acid-binding agent is usually introduced in the prior art to neutralize the acid generated in the reaction, thereby promoting the forward movement of the reaction. When the inventor of the application examines the influence of different acid-binding agents on reaction yield and purity, the inventor unexpectedly finds that when 4-dimethylaminopyridine is used as the acid-binding agent, the reaction yield can be remarkably improved compared with the conventional acid-binding agents such as triethylamine, DIPEA, sodium bicarbonate and the like.
In addition, the inventors of the present application examined the influence of different solvents on the yield and purity of the product by using chloroform as a main solvent in the mixed solvent of Paraqing et al (pesticide, 2006, 45 (6): 385-386, 391) in the prior art (in this document, the purity of the bromination reaction is 95%, the yield is 98%, which is remarkably higher than that reported in other documents), and found that the yield and purity are optimal when tetrahydrofuran and carbon tetrachloride are used as the mixed solvent in the catalyst system of the present invention.
In another aspect of the invention, a preparation method of a chlorfenapyr intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile is provided, which comprises the following steps:
1) in a mixed solvent, under the existence of a catalyst and an acid-binding agent, carrying out bromination reaction on 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile and bromine to prepare an intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile;
the specific reaction formula is as follows:
Figure BDA0003596371520000051
preferably, the mixed solvent in step 1) is a mixed solvent of tetrahydrofuran and another inert solvent.
Suitable inert solvents are aliphatic hydrocarbons, preferably aliphatic C5-C16Hydrocarbons, more preferably C5-C16Alkanes, or C5-C16Cycloalkanes such as pentane, hexane, cyclohexane or petroleum ether; halogenated hydrocarbons, preferably halogenAliphatic C1-C6Alkanes, or halogenated aromatic C6-C10Hydrocarbons, e.g. CH2Cl2、CHCl3、CCl4、CH2ClCH2Cl、CCl3CH3、CHCl2CH2Cl、CCl2CCl2Or chlorobenzene; ethers, preferably C1-C6Cycloalkyl ether, C1-C6alkyl-C1-C6Alkyl ethers, C1-C6alkyl-C3-C6Cycloalkyl ether, C1-C6polyol-C1-C6Alkyl ethers and C1-C6alkyl-C6-C10Aryl ethers, e.g. CH3CH2OCH2CH3、(CH3)2CHOCH(CH3)2、CH3OC(CH3)3(MTBE)、CH3OCH3(DME)、CH3OCH2CH2OCH3、CH3OC(CH3)2CH2CH3And diethylene glycol; esters, preferably aliphatic C1-C6Alcohols with aliphatic C1-C6Esters of carboxylic acids, aromatic C6-C10Alcohols with aromatic C6-C10Esters of carboxylic acids, omega-hydroxy-C1-C6Cyclic esters of carboxylic acids, e.g. CH3C (O) OCH2CH3、CH3C(O)OCH3、CH3C(O)OCH2CH2CH2CH3、CH3C(O)OCH(CH3)CH2CH3、CH3C(O)OC(CH3)、CH3CH2CH2C(O)OCH2CH3、CH3CH(OH)C(O)OCH2CH3、CH3CH(OH)C(O)OCH3、CH3C(O)OCH2CH(CH3)2、CH3C(O)OCH(CH3)2、CH3CH2C(O)OCH3Benzyl benzoate and gamma-butyrolactone; carbonates, e.g. ethylene carbonate, propylene carbonate, CH3CH2OC(O)OCH2CH3And CH3OC(O)OCH3(ii) a Nitriles, preferably C1-C6Nitriles, e.g. ACN and CH3CH2CN; alcohols, preferably C1-C4Alcohols and C2-C4Alkanediols, e.g. CH3OH、CH3CH2OH、CH3CH2CH2OH、CH3CH(OH)CH3、CH3(CH2)3OH and C (CH)3)3OH、CH2(OH)CH2(OH)、CH3CH(OH)CH2OH; amide and urea derivatives, preferably DMF, NMP, DMA, DMI, DMPU, HMPA; in addition, DMSO and sulfolane.
More preferably, the mixture solvent in the step 1) is a mixture solvent of tetrahydrofuran and carbon tetrachloride; most preferably, in the mixed solvent, the volume ratio of tetrahydrofuran to carbon tetrachloride is 5: 1-2.
Preferably, the catalyst in the step 1) is iron powder, manganese dioxide or iron tribromide; more preferably iron powder.
Preferably, the acid-binding agent in the step 1) is selected from 4-dimethylaminopyridine, DIPEA, triethylamine, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; most preferably, the acid scavenger is selected from 4-dimethylaminopyridine.
Preferably, the molar ratio of the 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile, the bromine, the catalyst and the acid-binding agent in the step 1) is 1:1.0-2.0:0.1-0.2:1.0-3.0, and more preferably, the molar ratio is 1:1.0-1.2:0.1-0.15: 1.0-1.5.
Preferably, the reaction temperature of step 1) is 30-60 ℃, more preferably 40-50 ℃;
preferably, the reaction time of step 1) is 2 to 10 hours, more preferably 3 to 5 hours.
The reaction mixture of step 1) can be worked up in a conventional manner, for example by mixing with water, separating the phases and, if appropriate, purifying the crude product in a conventional manner. The solvent is generally removed from the reaction mixture by distillation after the reaction of step 1) is complete. Alternatively, it is also possible to add water to the mixture after the reaction is complete, to remove part of the solvent by distillation, to remove the aqueous layer and to dry the organic layer containing the compound of formula III, for example by adding hygroscopic material. The product of step 1) can also be obtained by crystallization from the organic layer or by removal of the organic solvent.
Preferably, the post-treatment method of step 1) is as follows: and cooling the reaction liquid, adding water, stirring, distilling to remove the mixed solvent, separating out a large amount of light yellow solid in the water phase, filtering, washing the filter cake with water for three times, collecting the filter cake, and drying to obtain the intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile.
Compared with the prior art, the invention has the beneficial effects that:
(1) compared with the method for preparing the chlorfenapyr in the prior art, the method has the advantages that the yield of the intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile is higher, and the reaction cost is reduced;
(2) the method has simple reaction steps and mild reaction conditions, and simultaneously, the reagents used in the reaction are cheap and easily available, so that the method is easy to realize industrialization.
(3) The method has high product purity, can realize high-purity products by simple post-treatment, and saves subsequent purification steps.
Detailed Description
The present invention will be described in detail with reference to examples. In the present invention, the following examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Figure BDA0003596371520000071
In a 500mL reaction flask, 27.1g (about 0.1mol) of 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile was charged, dissolved with 200mL of tetrahydrofuran and 50mL of carbon tetrachloride, followed by addition of 0.6g of iron powder and 14.7g (about 0.12mol) of 4-dimethylaminopyridine, and stirring was carried out for 30 min. Then, 19.8g (about 0.11mol) of liquid bromine is slowly dropped into the mixture, the temperature is controlled to be between 40 and 50 ℃, and the reaction is carried out for 4 hours at room temperature after the dropping. After the reaction is finished, cooling the reaction liquid, adding water, stirring, distilling to remove the mixed solvent, separating out a large amount of light yellow solid in the water phase, filtering, washing the filter cake with water for three times, collecting the filter cake, and drying to obtain 33.2g of yellow white solid 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile, wherein the purity of the product is 98.5% by HPLC detection, and the yield is 95.0%.
Examples 2-5 effect of different solvents on reaction yield and product purity.
Example 2
The difference from example 1 is that 250mL of tetrahydrofuran was used instead of 200mL of tetrahydrofuran and 50mL of carbon tetrachloride, and the other conditions were the same as example 1.
Example 3
The difference from example 1 is that 250mL of carbon tetrachloride is used instead of 200mL of tetrahydrofuran and 50mL of carbon tetrachloride, and the other conditions are the same as example 1.
Example 4
The difference from example 1 is that 200mL of tetrahydrofuran and 50mL of carbon tetrachloride were replaced with 200mL of carbon tetrachloride and 50mL of tetrahydrofuran, and the other conditions were the same as in example 1.
Example 5
The difference from example 1 is that 200mL of tetrahydrofuran and 50mL of carbon tetrachloride were replaced with 200mL of tetrahydrofuran and 50mL of chlorobenzene, and the other conditions were the same as in example 1.
The yield and purity data for examples 2-5 are shown below:
example numbering Purity (%) Yield (%)
Example 2 96.8 91.8
Example 3 95.7 92.5
Example 4 93.0 88.1
Example 5 93.8 82.3
As can be seen from examples 1-5, when tetrahydrofuran and carbon tetrachloride were used as the mixed solvent, the yield and purity of the product were greatly improved.
Examples 6-9 effects of different acid scavengers on reaction yield and product purity.
Example 6
The difference from example 1 was that 14.7g of 4-dimethylaminopyridine was replaced with 14.7g of DIPEA and the other conditions were the same as in example 1.
Example 7
The difference from example 1 is that 14.7g of 4-dimethylaminopyridine was replaced with 14.7g of triethylamine under the same conditions as in example 1.
Example 8
The difference from example 1 is that 14.7g of 4-dimethylaminopyridine was replaced with 14.7g of sodium hydrogencarbonate and the other conditions were the same as in example 1.
Example 9
The difference from example 1 is that 14.7g of 4-dimethylaminopyridine was replaced with 14.7g of sodium carbonate and the other conditions were the same as in example 1.
The yield and purity data for examples 6-9 are shown below:
example numbering Purity (%) Yield (%)
Example 6 95.3 86.3
Example 7 93.6 82.7
Example 8 94.2 76.3
Example 9 92.6 79.8
As can be seen from examples 1 and 6-9, when 4-dimethylaminopyridine is used as an acid-binding agent, the yield and the purity of the product are both greatly improved.
Examples 10-12 effect of different catalysts on reaction yield and product purity.
Example 10
The difference from example 1 is that 0.1mol of manganese dioxide is used instead of 0.1mol of iron powder, and the other conditions are the same as example 1.
Example 11
Except for using 0.1mol of iron tribromide instead of 0.1mol of iron powder in example 1, the other conditions were the same as in example 1.
Example 12
The difference from example 1 is that no catalyst was added and the other conditions were the same as in example 1.
The yield and purity data for examples 10-12 are shown below:
example numbering Purity (%) Yield (%)
Example 10 94.5 88.7
Example 11 95.1 85.3
Example 12 93.2 74.7
As can be seen from examples 1 and 10-12, the yield and purity of the product are greatly improved when iron powder is used as the catalyst.
Example 13 Synthesis of Chlorfenapyr
17.5g (0.05mol) of 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile was charged into a 300mL reaction flask, followed by addition of 70mL of tetrahydrofuran, stirring for dissolution, slowly dropwise addition of 70mL of tetrahydrofuran containing 3.0g (60%, 0.075mol) of sodium hydride, stirring for reaction at 30 ℃ for 0.5h, dropwise addition of 12.9g (0.10mol) of bromochloromethane, reaction at 60 ℃ for 6h, treatment with a tetrahydrofuran solution containing 7.5g (0.12mol) of sodium ethoxide, reaction at 60 ℃ for 7h, cooling, filtration, solvent removal, and recrystallization from a mixed solvent of n-hexane and ethyl acetate to give 18.6g of white solid bromothalonil in a yield of 91.3%.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (10)

1. A method for preparing chlorfenapyr, comprising the steps of:
1) in a mixed solvent, in the presence of a catalyst and an acid-binding agent, carrying out bromination reaction on 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile and bromine to prepare an intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile;
2) respectively reacting 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile with chlorobromomethane and sodium ethoxide under the action of alkali, and performing post-treatment to obtain a target product, namely chlorfenapyr;
the specific reaction formula is as follows:
Figure FDA0003596371510000011
2. the method for preparing chlorfenapyr according to claim 1, characterized in that: the mixed solvent in the step 1) is a mixed solvent of tetrahydrofuran and another inert solvent; preferably, the mixture solvent in the step 1) is a mixture solvent of tetrahydrofuran and carbon tetrachloride; preferably, in the mixed solvent, the volume ratio of tetrahydrofuran to carbon tetrachloride is 5: 1-2.
3. The process for preparing chlorfenapyr according to claim 1 or 2, characterized in that: the catalyst in the step 1) is iron powder, manganese dioxide or ferric tribromide; more preferably iron powder.
4. The method for preparing chlorfenapyr according to claim 1 or 2, characterized in that: the acid-binding agent in the step 1) is selected from 4-dimethylamino pyridine, DIPEA, triethylamine, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; most preferably, the acid scavenger is selected from 4-dimethylaminopyridine.
5. The method for preparing chlorfenapyr according to claim 1, characterized in that: the mixture solvent in the step 1) is a mixed solvent of tetrahydrofuran and carbon tetrachloride; and in the mixed solvent, the volume ratio of tetrahydrofuran to carbon tetrachloride is 5: 1-2; the catalyst in the step 1) is iron powder; the acid-binding agent in the step 1) is 4-dimethylamino pyridine.
6. The method for preparing chlorfenapyr according to claim 1, characterized in that: the molar ratio of the 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile, the bromine, the catalyst and the acid-binding agent in the step 1) is 1:1.0-2.0:0.1-0.2:1.0-3.0, preferably, the molar ratio is 1:1.0-1.2:0.1-0.15: 1.0-1.5;
preferably, the reaction temperature of step 1) is 30-60 ℃, more preferably 40-50 ℃; the reaction time in step 1) is 2 to 10 hours, more preferably 3 to 5 hours.
7. The method for preparing chlorfenapyr according to claim 1, characterized in that: the reaction process of the step 2) is as follows: dissolving 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile in tetrahydrofuran, slowly dropwise adding tetrahydrofuran containing sodium hydride, stirring for reaction, dropwise adding bromochloromethane, continuing to react, treating with tetrahydrofuran solution containing sodium ethoxide, reacting for a period of time, detecting the reaction process by TLC, cooling, filtering after the reaction is finished, removing the solvent, and recrystallizing with n-hexane/ethyl acetate mixed solvent to obtain white solid chlorfenapyr.
8. A method for preparing a chlorfenapyr intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile is characterized by comprising the following steps: which comprises the following steps:
in a mixed solvent, under the existence of a catalyst and an acid-binding agent, carrying out bromination reaction on 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile and bromine to prepare an intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile;
the specific reaction formula is as follows:
Figure FDA0003596371510000021
9. the process of claim 8 for the preparation of the fipronil intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile, characterized in that: the mixture solvent is a mixed solvent of tetrahydrofuran and carbon tetrachloride; and in the mixed solvent, the volume ratio of tetrahydrofuran to carbon tetrachloride is 5: 1-2; the catalyst is iron powder; the acid-binding agent is 4-dimethylamino pyridine.
10. The process for the preparation of the fipronil intermediate 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile according to claim 8 or 9, characterized in that: the molar ratio of the 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-nitrile to the bromine to the catalyst to the acid-binding agent is 1:1.0-2.0:0.1-0.2:1.0-3.0, preferably 1:1.0-1.2:0.1-0.15: 1.0-1.5; the reaction temperature is 30-60 ℃, and more preferably 40-50 ℃; the reaction time is 2 to 10 hours, more preferably 3 to 5 hours.
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