CN110845340B - Preparation method of fipronil intermediate - Google Patents
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Abstract
The invention relates to a preparation method of a fipronil intermediate, which comprises the following steps: chlorination reaction is carried out on 4-methylaniline to prepare 2, 6-dichloro-4-trichloromethylaniline; the 2, 6-dichloro-4-trichloromethylaniline is subjected to fluoro reaction to prepare the 2, 6-dichloro-4-trifluoromethylaniline, namely the fipronil intermediate finished product. The invention provides a brand-new preparation method of 2, 6-dichloro-4-trifluoromethyl aniline, which has the advantages of easily obtained starting materials, short reaction steps, clear mechanism, less side reactions, high product yield and contribution to realizing industrialization; the average yield of the method is not lower than 90%, and the product purity is more than 99.0%.
Description
Technical Field
The invention relates to a preparation method of a fipronil intermediate, which is specifically 2, 6-dichloro-4-trifluoromethylaniline and belongs to the technical field of intermediate compound preparation.
Background
To the best of the applicant's knowledge, 2, 6-dichloro-4-trifluoromethylaniline is an important intermediate in the synthesis of the insecticide fipronil, which is white or off-white in appearance and has a melting point of 35-37 ℃.
The literature and patents at present report various synthetic methods of 2, 6-dichloro-4-trifluoromethylaniline, and the methods mainly have two technical problems: firstly, the reaction pressure is high, the yield is low, and industrialization is difficult to realize; secondly, reaction byproducts are more and difficult to purify, and the obtained product is liquid with the purity of only about 90 percent.
The U.S. patent application with publication number of US5401882A and the chinese invention patent application with publication number of CN1436769A respectively propose that 2-chloro-4-trifluoromethyl-N, N-dimethylaniline is used as a raw material, and 2, 6-dichloro-4-trifluoromethylaniline is obtained through chlorination and demethylation reactions. The technical scheme has the disadvantages that: (1) the raw materials are difficult to obtain and need to be prepared by high-pressure reaction; (2) the chlorination and demethylation reaction are operated by a one-pot method, the mechanism is complex, the side reaction is more, the obtained product is difficult to purify, and the purity and yield of the intermediate pyrazole ring in the next step are influenced.
The Chinese patent with the publication number of CN100534975C proposes that 4-trifluoromethyl aniline is used as a raw material to be directly chlorinated to obtain 2, 6-dichloro-4-trifluoromethyl aniline. The technical scheme is simple, the reaction mechanism is clear, but the price of the raw material 4-trifluoromethyl aniline is high and exceeds the price of the product, and obviously, the method cannot be used for large-scale production.
The Chinese patent with the publication number of CN101289401B proposes that 3,4, 5-trifluorotoluene is used as a raw material, and ammonia gas is directly introduced to prepare 2, 6-dichloro-4-trifluoromethylaniline. However, the ammonia introduction condition of the technical scheme is harsh, the reaction pressure is above 10MPa, the safety risk of large-scale production is high, the reaction selectivity is poor, a plurality of isomers are generated, and the product is difficult to purify.
The invention patent in China with the grant publication number CN104072379B adopts aniline as a raw material, and 2, 6-dichloro-4-trifluoromethyl aniline is obtained through acetylation, trifluoromethylation, chlorination and deprotection. According to the technical scheme, gas trifluorobromotrifluoromethane is used as a trifluoride reagent and needs to react in a pressure vessel, but the trifluorobromotrifluoromethane has a strong corrosion effect on common metals and has higher requirements on large-scale production equipment.
Disclosure of Invention
The main purposes of the invention are: the problems in the prior art are solved, and the preparation method of the fipronil intermediate is provided, so that the 2, 6-dichloro-4-trifluoromethylaniline can be better prepared.
The technical scheme for solving the technical problems of the invention is as follows:
a preparation method of a fipronil intermediate is characterized by comprising the following steps:
firstly, chlorination reaction is carried out on 4-methylaniline to prepare 2, 6-dichloro-4-trichloromethylaniline;
and secondly, carrying out fluoro reaction on the 2, 6-dichloro-4-trichloromethylaniline to prepare the 2, 6-dichloro-4-trifluoromethylaniline, namely the fipronil intermediate finished product.
The method has the advantages of easily obtained starting materials, short reaction steps, clear mechanism, less side reactions, high product yield and contribution to realizing industrialization.
The technical scheme of the invention is further perfected as follows:
preferably, the specific process of the first step is as follows: taking a solvent, 4-methylaniline and a catalyst, uniformly mixing, then adding a chlorination reagent for chlorination reaction, and removing the solvent and purifying a reaction product to obtain the 2, 6-dichloro-4-trichloromethylaniline.
More preferably, in the first step, the solvent is an inert solvent; the equivalent ratio of the 4-methylaniline, the catalyst and the chlorinated reagent is 1 (0.01-0.1) to 5.0-8.0); the temperature of the chlorination reaction is 10-150 ℃, and the reaction time of the chlorination reaction is 2-12 hours; the chlorinating agent is chlorine; the catalyst is azodiisobutyronitrile, dibenzoyl peroxide or azodiisoheptonitrile; the end point of the chlorination reaction is the end of the reaction when the conversion of 4-methylaniline is greater than 98%.
More preferably, in the first step, the inert solvent is dichloroethane, chloroform, or carbon tetrachloride.
More preferably, in the first step, the equivalent ratio of the 4-methylaniline, the catalyst and the chlorinating agent is 1 (0.01-0.03) to (5.0-6.5); the temperature of the chlorination reaction is 30-50 ℃, and the reaction time of the chlorination reaction is 3-5 hours; the catalyst is azodiisobutyronitrile; the end point of the chlorination reaction is the end of the reaction when the conversion of 4-methylaniline is greater than 99%.
More preferably, in the first step, the specific process of desolvating and purifying the reaction product is as follows: decompression desolventizing, cooling crystallization and suction filtration.
By adopting the preferred scheme, the 2, 6-dichloro-4-trichloromethyl aniline can be prepared better.
Preferably, the specific process of the second step is as follows:
taking a solvent and 2, 6-dichloro-4-trichloromethylaniline, uniformly mixing, then adding a fluoro reagent and a catalyst for fluoro reaction, desolventizing and purifying a reaction product to obtain the 2, 6-dichloro-4-trifluoromethylaniline.
More preferably, in the second step, the solvent is ethylene glycol, DMF, or DMSO; the equivalent ratio of the 2, 6-dichloro-4-trichloromethylaniline, the catalyst and the fluoro reagent is 1 (0.005-0.05) to 1.0-5.0; the temperature of the fluorination reaction is 0-150 ℃, and the time of the fluorination reaction is 1-10 hours; the fluorinating agent is potassium fluoride or cesium fluoride; the catalyst is tetramethyl ammonium bromide, tetrabutyl ammonium bromide or triethylene diamine; the end point of the fluorination reaction is the end of the reaction when the conversion of 2, 6-dichloro-4-trichloromethylaniline is greater than 99%.
More preferably, in the second step, the solvent is DMF; the equivalent ratio of the 2, 6-dichloro-4-trichloromethylaniline, the catalyst and the fluoro reagent is 1 (0.01-0.02) to 1.1-1.5); the temperature of the fluorination reaction is 80-110 ℃, and the time of the fluorination reaction is 4-6 hours; the fluorinating reagent is potassium fluoride; the catalyst is triethylene diamine; the end point of the fluorination reaction is the end of the reaction when the conversion of 2, 6-dichloro-4-trichloromethylaniline is greater than 99.5%.
More preferably, in the second step, the specific process of desolvating and purifying the reaction product is: decompression desolventizing, and high vacuum distillation, wherein the vacuum degree is less than or equal to 1 mmHg.
By adopting the preferred scheme, the fipronil intermediate finished product can be prepared better: 2, 6-dichloro-4-trifluoromethylaniline.
Compared with the prior art, the invention provides a brand-new preparation method of 2, 6-dichloro-4-trifluoromethylaniline, which has the advantages of easily obtained starting materials, short reaction steps, clear mechanism, less side reactions, high product yield and contribution to realizing industrialization; the average yield of the method is not lower than 90%, and the product purity is more than 99.0%.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 2, 6-dichloro-4-trichloromethylaniline in example 1 of the present invention (1H NMR(CDCl3))。
FIG. 2 is a nuclear magnetic hydrogen spectrum of 2, 6-dichloro-4-trifluoromethylaniline of example 1 of the present invention (1H NMR(CDCl3))。
Detailed Description
The preparation method of the fipronil intermediate specifically implemented by the invention comprises the following steps:
firstly, chlorination reaction is carried out on 4-methylaniline to prepare 2, 6-dichloro-4-trichloromethylaniline;
and secondly, carrying out fluoro reaction on the 2, 6-dichloro-4-trichloromethylaniline to prepare the 2, 6-dichloro-4-trifluoromethylaniline, namely the fipronil intermediate finished product.
The specific process of the first step is as follows: in a reaction vessel, taking a solvent, 4-methylaniline and a catalyst, uniformly mixing, then adding a chlorinated reagent for chlorination reaction, desolventizing and purifying a reaction product to obtain the 2, 6-dichloro-4-trichloromethylaniline.
Specifically, in the first step:
the solvent is inert solvent, and the inert solvent is dichloroethane, chloroform or carbon tetrachloride.
The equivalent ratio of the 4-methylaniline, the catalyst and the chlorinating agent is 1 (0.01-0.1) to (5.0-8.0), or 1 (0.01-0.03) to (5.0-6.5).
The temperature of the chlorination reaction is 10-150 ℃, or 30-50 ℃; the reaction time of the chlorination reaction is 2 to 12 hours, or 3 to 5 hours.
The chlorinating agent is chlorine gas.
The catalyst is azobisisobutyronitrile, dibenzoyl peroxide, or azobisisoheptylcyanide, such as azobisisobutyronitrile.
The end point of the chlorination reaction is when the reaction is complete at a 4-methylaniline conversion greater than 98% (e.g., greater than 99%). Note: HPLC can be used to monitor 4-methylaniline conversion.
The specific process of desolventizing and purifying the reaction product comprises the following steps: decompression desolventizing, cooling crystallization and suction filtration.
The second step is specifically as follows: in a reaction vessel, taking a solvent and 2, 6-dichloro-4-trichloromethylaniline, uniformly mixing, then adding a fluoro reagent and a catalyst for fluoro reaction, desolventizing and purifying a reaction product to obtain the 2, 6-dichloro-4-trifluoromethylaniline.
Specifically, in the second step:
the solvent is ethylene glycol, DMF, or DMSO, such as DMF.
The equivalent ratio of the 2, 6-dichloro-4-trichloromethylaniline, the catalyst and the fluoro reagent is 1 (0.005-0.05): (1.0-5.0), or 1 (0.01-0.02): 1.1-1.5.
The temperature of the fluorination reaction is 0-150 ℃, or 80-110 ℃, and the time of the fluorination reaction is 1-10 hours, or 4-6 hours.
The fluorinating agent is potassium fluoride or cesium fluoride, for example potassium fluoride.
The catalyst is tetramethylammonium bromide, tetrabutylammonium bromide, or a triethylenediamine, such as triethylenediamine.
The end point of the fluorination reaction is the end of the reaction when the conversion of 2, 6-dichloro-4-trichloromethylaniline is greater than 99% (e.g., greater than 99.5%). Note: HPLC can be used to monitor the conversion of 2, 6-dichloro-4-trichloromethylaniline.
The specific process of desolventizing and purifying the reaction product comprises the following steps: decompression desolventizing and vacuum distillation.
The invention is described in further detail below with reference to embodiments and with reference to the drawings. The invention is not limited to the examples given.
Example 1
107.1g (1mol, 1.0eq) of 4-methylaniline, 3.3g (0.02mol, 0.02eq) of azodiisobutyronitrile as a catalyst and 500g of dichloroethane as a solvent are added into a 1000ml four-port bottle, stirred, heated to 30 ℃, introduced with 426g (6mol, 6.0eq) of chlorine as a chlorinating reagent at 30-50 ℃, and kept at 30-50 ℃ for 4 hours after the introduction. Using HPLC to control, stopping the reaction when the content of 4-methylaniline is less than 1%, carrying out decompression desolvation, cooling crystallization, and carrying out suction filtration to obtain 273.8g of 2, 6-dichloro-4-trichloromethylaniline with the purity: 99.2%, yield: 98 percent. The nuclear magnetic hydrogen spectrum of the 2, 6-dichloro-4-trichloromethyl aniline is shown in figure 1.
273.8g (0.98mol, 1.0eq) of 2, 6-dichloro-4-trichloromethylaniline and 550g of DMF (solvent) are added into a 2000ml four-necked bottle, stirring is started, 68.3g (1.18mol, 1.2eq) of potassium fluoride as a fluoro reagent and 1.1g (0.0098mol, 0.01eq) of triethylene diamine as a catalyst are added after the raw materials are dissolved, the temperature is raised to 100 ℃, the reaction is kept for 5 hours by HPLC (high performance liquid chromatography), when the concentration of 2, 6-dichloro-4-trichloromethylaniline is less than 0.5 percent, the reaction is stopped, the pressure is reduced for desolventizing, the high vacuum distillation is carried out under the vacuum degree of 1mmHg, and 209.3g of the product 2, 6-dichloro-4-trifluoromethylaniline is obtained, and the purity: 99.4%, yield: 92.9%, two-step overall yield: 91.0 percent. The nuclear magnetic hydrogen spectrum of the 2, 6-dichloro-4-trifluoromethylaniline is shown in FIG. 2.
The synthetic route of this example is:
example 2
107.1g (1mol, 1.0eq) of 4-methylaniline, 4.8g (0.02mol, 0.02eq) of dibenzoyl peroxide as a catalyst and 450g of chloroform as a solvent are added into a 1000ml four-port bottle, stirred, heated to 30 ℃, introduced with 462g (6.5mol, 6.0eq) of chlorine as a chlorinating reagent at 30-50 ℃, and kept for reaction for 5 hours at 30-50 ℃ after the introduction. And (3) performing HPLC (high performance liquid chromatography) control, stopping the reaction when the content of 4-methylaniline is less than 1%, performing reduced pressure desolvation, cooling and crystallization, and performing suction filtration to obtain 271g of 2, 6-dichloro-4-trichloromethylaniline with the purity: 99.0%, yield: 97 percent. The nuclear magnetic hydrogen spectrum of the 2, 6-dichloro-4-trichloromethylaniline is consistent with that of example 1.
271g (0.97mol, 1.0eq) of 2, 6-dichloro-4-trichloromethylaniline and 500g of solvent DMSO are added into a 2000ml four-neck flask, stirring is started, after the raw materials are dissolved, 84.5g (1.46mol, 1.5eq) of fluorizating reagent potassium fluoride and 3.1g (0.0097mol, 0.01eq) of tetrabutylammonium bromide serving as a catalyst are added, the temperature is increased to 110 ℃, the reaction is kept for 6 hours by HPLC (high performance liquid chromatography) control, when the content of 2, 6-dichloro-4-trichloromethylaniline is less than 0.5 percent, the reaction is stopped, the desolvation is carried out under reduced pressure, the high vacuum distillation is carried out under the vacuum degree of 1mmHg, and 207g of the product 2, 6-dichloro-4-trifluoromethylaniline is obtained, and the purity: 99.1%, yield: 92.8%, two-step total yield: 90.0 percent. The nuclear magnetic hydrogen spectrum of the 2, 6-dichloro-4-trifluoromethylaniline corresponds to that of example 1.
Example 3
107.1g (1mol, 1.0eq) of 4-methylaniline, 9.3g (0.03mol, 0.03eq) of azodiisoheptacyanic catalyst and 500g of carbon tetrachloride solvent are added into a 1000ml four-port bottle, stirred, heated to 30 ℃, introduced with 391g (5.5mol, 5.5eq) of chlorine chloride reagent at 30-50 ℃, and kept at 30-50 ℃ for 4 hours after the introduction. Using HPLC to control, stopping the reaction when the content of 4-methylaniline is less than 1%, carrying out vacuum desolventizing, cooling and crystallizing, and carrying out suction filtration to obtain 272.4g of 2, 6-dichloro-4-trichloromethylaniline with the purity: 99.1%, yield: 97.5 percent. The nuclear magnetic hydrogen spectrum of the 2, 6-dichloro-4-trichloromethylaniline is consistent with that of example 1.
Adding 272.4g (0.975mol, 1.0eq) of 2, 6-dichloro-4-trichloromethylaniline and 550g (1.975 mol) of ethylene glycol as a solvent into a 2000ml four-neck flask, starting stirring, adding 207g (1.365mol, 1.4eq) of cesium fluoride as a fluoro reagent and 3.0g (0.0195mol, 0.02eq) of tetramethylammonium bromide as a catalyst after the raw materials are dissolved, heating to 120 ℃, keeping the temperature for reaction for 5 hours, stopping the reaction when the content of 2, 6-dichloro-4-trichloromethylaniline is less than 0.5% by HPLC (high performance liquid chromatography), carrying out reduced pressure desolventization, carrying out high vacuum distillation under the vacuum degree of 1mmHg to obtain 208.2g of the product 2, 6-dichloro-4-trifluoromethylaniline with the purity: 99.2%, yield: 92.8%, two-step total yield: 90.5 percent. The nuclear magnetic hydrogen spectrum of the 2, 6-dichloro-4-trifluoromethylaniline corresponds to that of example 1.
The invention also includes several other embodiments (numbered as examples 1 through 5) whose basic steps are the same as in embodiment 1, and the specific parameters of each step are shown in the following table.
The final products of 2, 6-dichloro-4-trifluoromethylaniline obtained in examples 1 to 5 above had a purity of 99.0% or more, and a total yield in two steps of 90% or more, respectively.
In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the claims of the present invention.
Claims (5)
1. A preparation method of a fipronil intermediate is characterized by comprising the following steps:
firstly, chlorination reaction is carried out on 4-methylaniline to prepare 2, 6-dichloro-4-trichloromethylaniline;
secondly, carrying out fluoro reaction on the 2, 6-dichloro-4-trichloromethylaniline to prepare 2, 6-dichloro-4-trifluoromethylaniline, namely a fipronil intermediate finished product;
the specific process of the first step is as follows:
uniformly mixing a solvent, 4-methylaniline and a catalyst, adding a chlorination reagent for chlorination reaction, desolventizing and purifying a reaction product to obtain 2, 6-dichloro-4-trichloromethylaniline; wherein the solvent is an inert solvent, and the inert solvent is dichloroethane, chloroform or carbon tetrachloride; the equivalent ratio of the 4-methylaniline, the catalyst and the chlorinated reagent is 1 (0.01-0.1) to 5.0-8.0); the temperature of the chlorination reaction is 10-150 ℃, and the reaction time of the chlorination reaction is 2-12 hours; the chlorinating agent is chlorine; the catalyst is azodiisobutyronitrile, dibenzoyl peroxide or azodiisoheptonitrile; the end point of the chlorination reaction is that the reaction is finished when the conversion rate of the 4-methylaniline is more than 98 percent;
the second step is specifically as follows:
uniformly mixing a solvent and 2, 6-dichloro-4-trichloromethylaniline, then adding a fluoro reagent and a catalyst for fluoro reaction, desolventizing and purifying a reaction product to obtain 2, 6-dichloro-4-trifluoromethylaniline; wherein the solvent is ethylene glycol, DMF, or DMSO; the equivalent ratio of the 2, 6-dichloro-4-trichloromethylaniline, the catalyst and the fluoro reagent is 1 (0.005-0.05) to 1.0-5.0; the temperature of the fluorination reaction is 0-150 ℃, and the time of the fluorination reaction is 1-10 hours; the fluorinating agent is potassium fluoride or cesium fluoride; the catalyst is tetramethyl ammonium bromide, tetrabutyl ammonium bromide or triethylene diamine; the end point of the fluorination reaction is the end of the reaction when the conversion of 2, 6-dichloro-4-trichloromethylaniline is greater than 99%.
2. The process according to claim 1, wherein in the first step, the equivalent ratio of 4-methylaniline, catalyst and chlorinating agent is 1 (0.01-0.03) to (5.0-6.5); the temperature of the chlorination reaction is 30-50 ℃, and the reaction time of the chlorination reaction is 3-5 hours; the catalyst is azodiisobutyronitrile; the end point of the chlorination reaction is the end of the reaction when the conversion of 4-methylaniline is greater than 99%.
3. The method of claim 1, wherein the step of desolvating and purifying the reaction product comprises: decompression desolventizing, cooling crystallization and suction filtration.
4. The method according to claim 1, wherein in the second step, the solvent is DMF; the equivalent ratio of the 2, 6-dichloro-4-trichloromethylaniline, the catalyst and the fluoro reagent is 1 (0.01-0.02) to 1.1-1.5); the temperature of the fluorination reaction is 80-110 ℃, and the time of the fluorination reaction is 4-6 hours; the fluorinating reagent is potassium fluoride; the catalyst is triethylene diamine; the end point of the fluorination reaction is the end of the reaction when the conversion of 2, 6-dichloro-4-trichloromethylaniline is greater than 99.5%.
5. The method of claim 1, wherein the second step comprises the steps of desolvating and purifying the reaction product: decompression desolventizing, and high vacuum distillation, wherein the vacuum degree is less than or equal to 1 mmHg.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289400A (en) * | 2008-03-24 | 2008-10-22 | 浙江巍华化工有限公司 | Process for synthesizing 2,6- dichlor-4-trifluoromethyl aniline |
| CN103408437A (en) * | 2013-08-30 | 2013-11-27 | 江苏丰华化学工业有限公司 | Method for preparing 2,6-dichloro-4-trifluoromethyl phenylamine |
| CN103910639A (en) * | 2014-03-13 | 2014-07-09 | 凯美泰克（天津）化工科技有限公司 | A method of preparing 2,6-dichloro-4-trifluoromethyl phenylamine |
| CN107963993A (en) * | 2018-01-06 | 2018-04-27 | 江苏托球农化股份有限公司 | A kind of preparation method of high-purity ethiprole |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289400A (en) * | 2008-03-24 | 2008-10-22 | 浙江巍华化工有限公司 | Process for synthesizing 2,6- dichlor-4-trifluoromethyl aniline |
| CN103408437A (en) * | 2013-08-30 | 2013-11-27 | 江苏丰华化学工业有限公司 | Method for preparing 2,6-dichloro-4-trifluoromethyl phenylamine |
| CN103910639A (en) * | 2014-03-13 | 2014-07-09 | 凯美泰克（天津）化工科技有限公司 | A method of preparing 2,6-dichloro-4-trifluoromethyl phenylamine |
| CN107963993A (en) * | 2018-01-06 | 2018-04-27 | 江苏托球农化股份有限公司 | A kind of preparation method of high-purity ethiprole |
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