阅读说明：本技术 一种氟虫腈中间体的制备方法 (Preparation method of fipronil intermediate ) 是由 曾淼 徐剑锋 赵飞 孙思 程晓文 于 2019-11-07 设计创作，主要内容包括：本发明涉及一种氟虫腈中间体的制备方法,包括：将4-甲基苯胺经氯化反应制得2,6-二氯-4-三氯甲基苯胺；将2,6-二氯-4-三氯甲基苯胺经氟代反应制得2,6-二氯-4-三氟甲基苯胺,此即氟虫腈中间体成品。本发明提供了一种全新的2,6-二氯-4-三氟甲基苯胺的制备方法,该方法起始原料易得、反应步骤短、机理清晰,副反应少、产品收率高,利于实现产业化；该方法的平均收率不低于90％,产品纯度99.0％以上。(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%.)

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;

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.

2. The method for preparing the compound of claim 1, wherein 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.

3. The method according to claim 2, wherein 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%.

4. The method according to claim 3, wherein the inert solvent is dichloroethane, chloroform or carbon tetrachloride in the first step.

5. The process according to claim 3, 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%.

6. The method of claim 2, wherein the step of desolvating and purifying the reaction product comprises: decompression desolventizing, cooling crystallization and suction filtration.

7. The method of claim 1, wherein the second step is performed by:

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.

8. The method according to claim 7, wherein 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%.

9. The method according to claim 8, 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%.

10. The method of claim 7, 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.

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.