CN118772034A - A preparation process of 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile - Google Patents

Abstract

The present invention relates to the field of chemical synthesis, and in particular to a preparation process of 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-nitrile, wherein the preparation process uses p-chlorophenylglycine or p-chlorophenylglycine sodium salt as a raw material, reacts with trifluoroacetic acid and phosgene in the presence of phosphorus trichloride or phosphorus oxychloride, trifluoroacetylation to obtain N-p-chlorobenzyl trifluoroacetamide, and N-p-chlorobenzyl trifluoroacetamide undergoes 1,3 dipolar cycloaddition reaction with chloroacrylonitrile in the presence of ammonia or triethylamine, and obtains 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-nitrile in a region-oriented manner. This synthetic route process is simple, the process conditions are mild, the raw materials are easily available, and the impact on the environment is small; in addition, the product has a high yield of raw materials and is stable, and has a high industrial practical value.

Description

A preparation process of 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile

Technical Field

The invention relates to the field of chemical synthesis, and in particular to a preparation process of 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile.

Background Art

2-p-Chlorophenyl-5-(trifluoromethyl)-pyrrole-3-carbonitrile is a chemical synthetic compound. This compound is a synthetic intermediate of Dioxapyrrolomycin, a metabolite of the microorganism Streptomyces fumanus. Therefore, it has potential biological activity and is widely used as a key intermediate in the preparation of pesticides such as chlorfenapyr and trolopride.

Chlorfenapyr is a highly effective insecticide and acaricide widely used in agriculture; trofloxacin can effectively inhibit hard-shelled and soft-bodied invertebrates and can be used to control mollusks and ship antifouling.

At present, the synthesis methods of 2-p-chlorophenyl-5-(trifluoromethyl)-pyrrole-3-carbonitrile are generally divided into several methods: 1. Reaction of 2-p-chlorophenyl trifluoroacetamide carbonitrile with acyl chloride or trifluoromethylsulfonic acid to generate an oxazolamide derivative, which is then reacted with 2-chloroacrylonitrile under alkaline conditions to obtain the product; 2. Chlorination of p-chlorophenylacetamide derivatives to convert them into corresponding dichlorides, which are then directly reacted with acrylonitrile in the presence of DBU to obtain the product; 3. Using trifluoromethyl p-chlorobenzyl ketone as a raw material, it reacts with hydroxylamine to generate an oxime, which is further reacted with 2-chloroacrylonitrile under alkaline conditions to obtain the product.

The above methods have the following defects: In method 1, during the reaction process, alkyl acyl chloride and trifluoromethylsulfonic acid only play the role of mediators and do not form a new compound skeleton. They are expensive and difficult to recover, which will directly affect the cost of the product. Therefore, this route is not economical. Method 2 currently has no commercially applicable raw materials, and the conversion yield of the dichloride converted from the compound p-chlorophenylacetamide derivative with acrylonitrile in the cyclization reaction under DBU conditions is very low. Method 3 The raw materials are usually obtained by Grignard reaction of p-chlorobenzyl bromide and ethyl trifluoromethylacetate, and the Grignard reaction has high requirements for the water content of the environment, is difficult to control the reaction, and has strict requirements on temperature conditions.

Summary of the invention

In order to solve the above technical problems, the present invention provides a preparation process of 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile. The process method uses p-chlorophenylglycine and trifluoroacetic acid as raw materials, first prepares p-chlorobenzyl trifluoroacetamide, and then reacts with chloroacrylonitrile to undergo 1,3 dipolar cycloaddition reaction to obtain 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile in a regio-directional manner, thereby solving the problems of complex process, harsh process conditions, high raw material cost, low yield and great environmental impact in the traditional synthesis route.

This is achieved specifically through the following technical solutions:

A preparation process of 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile comprises the following steps:

S1. Add p-chlorophenylglycine, trifluoroacetic acid and acetonitrile into a reactor in sequence, add a catalyst into the reactor, stir evenly and heat to raise the temperature, dropwise add a mixture of solid phosgene and acetonitrile into the reactor and keep warm.

S2. Heat up, add the mixture of solid phosgene and acetonitrile dropwise into the reactor again and keep warm.

S3, sampling and testing, reducing the pressure in the reactor, recovering acetonitrile, obtaining N-p-chlorobenzyl trifluoroacetamide and weighing and measuring.

S4. Add N-p-chlorobenzyl trifluoroacetamide into the reaction kettle, add DMF and 2-chloroacrylonitrile in sequence, add additives to adjust the environment in the reaction kettle to weak alkalinity, heat up and keep warm.

S5, cooling, crystallization, filtering, obtaining 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile and weighing.

Preferably, the heating temperature in S1 is 50-55° C., the dropwise addition time of the mixed liquid is 6 hours, and the heat preservation time is 2 hours.

Preferably, the mass ratio of the mixed liquid solid phosgene to acetonitrile in S1 is 18:20-30, and the mass ratio of p-chlorophenylglycine, trifluoroacetic acid and acetonitrile is 25:23:65-85.

Preferably, the catalyst in S1 is phosphorus trichloride or phosphorus oxychloride, and the p-chlorophenylglycine can be replaced by p-chlorophenylglycine sodium salt.

Preferably, the heating temperature in S2 is 65-80° C., the dripping time of the mixed liquid is 3 hours, and the insulation time is 0.5-2 hours.

Preferably, the mass ratio of solid phosgene to acetonitrile in the mixed solution in S2 is 17:22-28.

Preferably, the temperature of DMF in S4 is lower than 5°C, the temperature of 2-chloroacrylonitrile is 20-25°C, the heating and insulation is 45-65°C, and the insulation time is 0.5-2 hours.

Preferably, the mass ratio of DMF to 2-chloroacrylonitrile in S4 is 21-26:3.

Preferably, the additive in S4 is ammonia or triethylamine, and the weakly alkaline environment has a pH value of 8-9.

Preferably, the mass ratio of the p-chlorophenylglycine to the 2-chloroacrylonitrile is 25:12.

After adopting the above technical solution, the beneficial effects of the present invention are:

1. Using p-chlorophenylglycine, trifluoroacetic acid, 2-chloroacrylonitrile and the like as reactants for the synthesis reaction has a low production cost and is suitable for large-scale industrial production;

2. The reaction synthesis route is simple, the process conditions are mild, the energy demand is small, the impact on the environment is small, and it is green and environmentally friendly;

3. Adopt a production process in which reactants are added in batches and adjust the reaction temperature accordingly to make the synthesis reaction more thorough and improve the utilization rate of reactants and the yield of products;

4. The reactant solvent acetonitrile can be smoothly recovered, so that the solvent can be reused repeatedly and the production cost can be reduced.

DETAILED DESCRIPTION

The features and exemplary embodiments of various aspects of the present invention will be described in detail below. In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only configured to explain the present invention and are not configured to limit the present invention. For those skilled in the art, the present invention can be implemented without the need for some of these specific details. The following description of the embodiments is only to provide a better understanding of the present invention by illustrating examples of the present invention.

Example 1

A preparation process of 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile is carried out according to the following steps:

S1. Add 50g of p-chlorophenylglycine, 46g of trifluoroacetic acid and 150g of acetonitrile to the reactor in sequence, add 20g of phosphorus trichloride as a catalyst to the reactor, stir evenly using the stirring mechanism in the reactor, heat the temperature in the reactor to 50°C by the heating system, and uniformly add a mixed solution of 36g of solid phosgene and 50g of acetonitrile to the reactor, the dropping time is 6 hours, and the temperature is kept for 2 hours after the dropping is completed.

In this process, the reactants are p-chlorophenylglycine and trifluoroacetic acid. Acetonitrile is used as a solvent for the reactants p-chlorophenylglycine and trifluoroacetic acid due to its good solubility of organic and inorganic substances. After the reactants, solvent and catalyst phosphorus trichloride are added into the reactor in sequence, the substances in the reactor are stirred evenly so that various substances are fully contacted, which is conducive to the reaction. The temperature in the reactor is further heated to 50° C. At this time, 36 g of solid phosgene and 50 g of acetonitrile are evenly mixed and then slowly and uniformly added dropwise into the reactor. Due to the temperature conditions in the reactor, the solid phosgene is first decomposed into phosgene in the reactor, and then trifluoroacetylated with the reactants p-chlorophenylglycine and trifluoroacetic acid under the condition of the catalyst phosphorus trichloride to generate N-p-chlorobenzyl trifluoroacetamide. The reaction formula is as follows:

During the dropwise addition of the solid phosgene and acetonitrile mixture, the temperature in the reactor was maintained constant, and the dropwise addition time was 6 hours. After the dropwise addition was completed, the mixture was kept warm for 2 hours to allow the reaction to be more complete.

Among them, the reactant chlorophenylglycine can be replaced by p-chlorophenylglycine sodium salt. Since chlorophenylglycine or p-chlorophenylglycine sodium salt is easier to obtain and has a lower cost, it can be used as a reactant to reduce the production cost to a certain extent.

The catalyst phosphorus trichloride can be replaced by phosphorus oxychloride, both of which can promote the rapid progress of the reaction.

S2. After the holding time is reached, the heating system of the reactor is started to heat the reactor to 70°C. At this time, a mixture of 34 g of solid phosgene and 50 g of acetonitrile is uniformly added dropwise to the reactor for 3 hours. After the addition is completed, the mixture is kept warm for 1 hour.

This process is a continuation of S1. As the reaction proceeds, the concentration of the reactants in the reactor decreases. At this time, the temperature in the reactor is raised to 70°C to increase the activity of the reactants. At this time, an acetonitrile solution of solid phosgene is added dropwise to promote further reaction of the reactants. After the addition is completed, the mixture is kept warm for a certain period of time to increase the utilization rate of the reactants.

By adding a mixed solution of solid phosgene and acetonitrile in stages, the reactants are given sufficient time to react, so that the reactants can fully contact and react with each other, thereby ensuring the adequacy of the synthesis reaction, improving the utilization rate of the reactants, and further improving the yield of the product.

S3. After the holding time is reached, a small amount of sample is extracted for testing to verify the completion of the reaction. When the verification is qualified, the pressure in the reactor is gradually reduced to complete the recovery of the solvent acetonitrile to obtain the reaction intermediate N-p-chlorobenzyl trifluoroacetamide, weigh it and record the data.

In this process, the completion of the reaction is determined by measuring the concentration of the reactant in the solvent acetonitrile. The specific operation method is: multiple sampling, the sampling interval is 10 minutes, and the concentration of the reactant trifluoroacetic acid in the sampled samples is measured by liquid chromatography. When the concentration of trifluoroacetic acid is less than 0.008 g/ml or the concentration of trifluoroacetic acid obtained by two consecutive measurements is unchanged, the reaction is determined to be completed.

After the reaction is completed, the pressure and temperature in the reactor are reduced, the acetonitrile solvent in the reactor is collected and reused, thereby reducing production costs, and the remaining reaction intermediate N-p-chlorobenzyl trifluoroacetamide in the reactor is collected and weighed.

S4. Add the N-p-chlorobenzyl trifluoroacetamide obtained by the reaction into a reactor, add 200g DMF into the reactor, and then drop 24g 2-chloroacrylonitrile into the reactor. After the dropwise addition is completed, introduce ammonia into the reactor, or add triethylamine into the reactor to adjust the environment in the reactor to a weak alkaline pH of 8-9, heat to 55°C and keep warm for 1 hour.

In this process, the reactants are N-p-chlorobenzyl trifluoroacetamide and 2-chloroacrylonitrile, and DMF is used as a solvent and catalyst. The reaction environment is adjusted to a weak alkaline state and heated. At this time, N-p-chlorobenzyl trifluoroacetamide undergoes a 1,3 dipolar cycloaddition reaction with chloroacrylonitrile to obtain 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile in a regio-directional manner. The reaction formula is as follows:

During the reaction, the temperature in the reactor was maintained at 55° C. and the reaction time was 1 hour to allow the reactants to react fully, thereby increasing the yield.

The temperature of DMF before being added into the reactor is lower than 5°C, and the temperature of 2-chloroacrylonitrile before being added into the reactor is 20-25°C.

S5. After the reaction is completed, the temperature and pressure in the reactor are lowered to allow the reaction product to be fully cooled and crystallized, and then filtered to obtain the final product 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile, which is collected and weighed, and the data is recorded.

Example 2

A preparation process of 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile is carried out according to the following steps:

S1. 50 g of p-chlorophenylglycine, 46 g of trifluoroacetic acid and 150 g of acetonitrile were added to the reactor in sequence, phosphorus trichloride as a catalyst was added to the reactor, the stirring mechanism in the reactor was used to stir evenly, the temperature in the reactor was heated to 70 ° C by the heating system, and a mixed solution of 70 g of solid phosgene and 100 g of acetonitrile was uniformly added dropwise to the reactor for 9 hours, and the mixture was kept warm for 3 hours after the addition was completed.

S2. After the holding time is reached, a small amount of sample is extracted for testing to verify the completion of the reaction. When the verification is qualified, the pressure in the reactor is gradually reduced to complete the recovery of the solvent acetonitrile to obtain the reaction intermediate N-p-chlorobenzyl trifluoroacetamide, weigh it and record the data.

S3. Add the N-p-chlorobenzyl trifluoroacetamide obtained by the reaction into a reactor, add 200g DMF into the reactor, and then drop 24g 2-chloroacrylonitrile into the reactor. After the dropwise addition is completed, introduce ammonia into the reactor, or add triethylamine into the reactor to adjust the environment in the reactor to a weak alkaline pH of 8-9, heat to 55°C and keep warm for 1 hour.

S4. After the reaction is completed, the temperature and pressure in the reactor are lowered to allow the reaction product to be fully cooled and crystallized, and then filtered to obtain the final product 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile, which is collected and weighed, and the data is recorded.

Example 3

This embodiment is based on the embodiment 1. In S1, the mass of acetonitrile added for the first time is adjusted to 130g. Specifically, 50g of p-chlorophenylglycine, 46g of trifluoroacetic acid and 130g of acetonitrile are added to the reactor in sequence, phosphorus trichloride as a catalyst is added to the reactor, and the mixture is stirred evenly by a stirring mechanism in the reactor. The temperature in the reactor is heated to 50°C by a heating system, and a mixed solution of 36g of solid phosgene and 50g of acetonitrile is uniformly added dropwise to the reactor for 6 hours. After the addition is completed, the mixture is kept warm for 2 hours.

The remaining conditions are the same as those in Example 1.

Example 4

This embodiment is based on the embodiment 1. In S1, the mass of acetonitrile added for the first time is adjusted to 170g. Specifically, 50g of p-chlorophenylglycine, 46g of trifluoroacetic acid and 170g of acetonitrile are added to the reactor in sequence, phosphorus trichloride as a catalyst is added to the reactor, the mixture is stirred evenly by a stirring mechanism in the reactor, the temperature in the reactor is heated to 50°C by a heating system, and a mixed solution of 36g of solid phosgene and 50g of acetonitrile is uniformly added dropwise to the reactor for 6 hours. After the addition is completed, the mixture is kept warm for 2 hours.

The remaining conditions are the same as those in Example 1.

Example 5

This embodiment is based on the embodiment 1. In S1, the reaction temperature is adjusted to 45°C. Specifically, 50g of p-chlorophenylglycine, 46g of trifluoroacetic acid and 150g of acetonitrile are added to the reactor in sequence, phosphorus trichloride catalyst is added to the reactor, and the stirring mechanism in the reactor is used to stir evenly. The temperature in the reactor is heated to 45°C by the heating system, and a mixed solution of 36g of solid phosgene and 50g of acetonitrile is uniformly added dropwise to the reactor for 6 hours. After the addition is completed, the mixture is kept warm for 2 hours.

The remaining conditions are the same as those in Example 1.

Example 6

This embodiment is based on the embodiment 1. In S1, the reaction temperature is adjusted to 55°C. Specifically, 50g of p-chlorophenylglycine, 46g of trifluoroacetic acid and 150g of acetonitrile are added to the reactor in sequence, phosphorus trichloride catalyst is added to the reactor, and the stirring mechanism in the reactor is used to stir evenly. The temperature in the reactor is heated to 55°C by the heating system, and a mixed solution of 36g of solid phosgene and 50g of acetonitrile is uniformly added dropwise to the reactor for 6 hours. After the addition is completed, the mixture is kept warm for 2 hours.

The remaining conditions are the same as those in Example 1.

Example 7

This embodiment is based on Embodiment 1. In S2, the reaction temperature is adjusted to 65°C. Specifically, the heating system of the reactor is started to heat the reactor temperature to 65°C. A mixture of 34 g of solid phosgene and 50 g of acetonitrile is uniformly added dropwise to the reactor for 3 hours. After the addition is completed, the mixture is kept warm for 1 hour.

The remaining conditions are the same as those in Example 1.

Example 8

This embodiment is based on Embodiment 1. In S2, the reaction temperature is adjusted to 75°C. Specifically, the heating system of the reactor is started to heat the reactor temperature to 75°C. A mixture of 34 g of solid phosgene and 50 g of acetonitrile is uniformly added dropwise to the reactor for 3 hours. After the addition is completed, the mixture is kept warm for 1 hour.

The remaining conditions are the same as those in Example 1.

Example 9

This embodiment is based on the embodiment 1. In S4, the reaction temperature is adjusted to 50°C. Specifically, the N-p-chlorobenzyl trifluoroacetamide obtained by the reaction is added into the reactor, 200g DMF is added into the reactor, and then 24g 2-chloroacrylonitrile is added dropwise into the reactor. After the addition is completed, ammonia gas is introduced into the reactor, or triethylamine is added into the reactor, so as to adjust the environment in the reactor to a weak alkaline pH value of 8-9, and the reactor is heated to 50°C and kept warm for 1 hour.

The remaining conditions are the same as those in Example 1.

Example 10

This embodiment is based on the embodiment 1. In S4, the reaction temperature is adjusted to 60°C. Specifically, the N-p-chlorobenzyl trifluoroacetamide obtained by the reaction is added into the reactor, 200g DMF is added into the reactor, and then 24g 2-chloroacrylonitrile is added dropwise into the reactor. After the addition is completed, ammonia gas is introduced into the reactor, or triethylamine is added into the reactor, so as to adjust the environment in the reactor to a weak alkaline pH value of 8-9, and the reactor is heated to 60°C and kept warm for 1 hour.

The remaining conditions are the same as those in Example 1.

Embodiment 11

This embodiment is based on Embodiment 2. In S1, the dropping time of the solid phosgene and acetonitrile mixture is adjusted to 8 hours, and the insulation time is adjusted to 2 hours. Specifically, 50 g of p-chlorophenylglycine, 46 g of trifluoroacetic acid and 150 g of acetonitrile are added to the reactor in sequence, phosphorus trichloride catalyst is added to the reactor, and the mixture is stirred evenly by the stirring mechanism in the reactor. The temperature in the reactor is heated to 70°C by the heating system, and a mixture of 70 g of solid phosgene and 100 g of acetonitrile is uniformly dropped into the reactor for 8 hours. After the dropping is completed, the mixture is kept warm for 2 hours.

The remaining conditions are the same as those in Example 2.

Example 12

This embodiment is based on Embodiment 2. In S1, the dropping time of the solid phosgene and acetonitrile mixture is adjusted to 10 hours, and the insulation time is adjusted to 4 hours. Specifically, 50 g of p-chlorophenylglycine, 46 g of trifluoroacetic acid and 150 g of acetonitrile are added to the reactor in sequence, phosphorus trichloride catalyst is added to the reactor, and the mixture is stirred evenly by the stirring mechanism in the reactor. The temperature in the reactor is heated to 70°C by the heating system, and a mixture of 70 g of solid phosgene and 100 g of acetonitrile is uniformly dropped into the reactor for 10 hours. After the dropping is completed, the mixture is kept warm for 4 hours.

The remaining conditions are the same as those in Example 2.

Comparative Example 1:

This comparative example is based on Example 1, with the following adjustments:

In S1, the added mass of acetonitrile was adjusted to 130 g, and the heating temperature was adjusted to 45°C;

In S2, the heating temperature is adjusted to 65°C;

In S4, the heating temperature is adjusted to 50°C.

Specifically, S1, 50g of p-chlorophenylglycine, 46g of trifluoroacetic acid and 130g of acetonitrile are added to the reactor in sequence, 20g of phosphorus trichloride is added to the reactor as a catalyst, and the stirring mechanism in the reactor is used to stir evenly, the temperature in the reactor is heated to 45°C by the heating system, and a mixed solution of 36g of solid phosgene and 50g of acetonitrile is uniformly added dropwise to the reactor for 6 hours, and the mixture is kept warm for 2 hours after the addition is completed.

S2. After the holding time is reached, the heating system of the reactor is started to heat the reactor to 65°C. At this time, a mixture of 34 g of solid phosgene and 50 g of acetonitrile is uniformly added dropwise to the reactor for 3 hours. After the addition is completed, the mixture is kept warm for 1 hour.

S4. Add the N-p-chlorobenzyl trifluoroacetamide obtained by the reaction into a reactor, add 200g DMF into the reactor, and then drop 24g 2-chloroacrylonitrile into the reactor. After the dropwise addition is completed, introduce ammonia into the reactor, or add triethylamine into the reactor to adjust the environment in the reactor to a weak alkaline pH of 8-9, heat to 50°C and keep warm for 1 hour.

The remaining conditions are the same as those in Example 1.

Comparative Example 2:

This comparative example is based on Example 1, with the following adjustments:

In S1, the added mass of acetonitrile was adjusted to 170 g, and the heating temperature was adjusted to 55°C;

In S2, the heating temperature is adjusted to 75°C;

In S4, the heating temperature is adjusted to 60°C.

Specifically, S1, 50g of p-chlorophenylglycine, 46g of trifluoroacetic acid and 170g of acetonitrile are added to the reactor in sequence, 20g of phosphorus trichloride is added to the reactor as a catalyst, and the stirring mechanism in the reactor is used to stir evenly, the temperature in the reactor is heated to 55°C by the heating system, and a mixed solution of 36g of solid phosgene and 50g of acetonitrile is uniformly added dropwise to the reactor for 6 hours, and the mixture is kept warm for 2 hours after the addition is completed.

S2. After the holding time is reached, the heating system of the reactor is started to heat the reactor to 75°C. At this time, a mixture of 34 g of solid phosgene and 50 g of acetonitrile is uniformly added dropwise to the reactor for 3 hours. After the addition is completed, the mixture is kept warm for 1 hour.

S4. Add the N-p-chlorobenzyl trifluoroacetamide obtained by the reaction into a reactor, add 200g DMF into the reactor, and then drop 24g 2-chloroacrylonitrile into the reactor. After the dropwise addition is completed, introduce ammonia into the reactor, or add triethylamine into the reactor to adjust the environment in the reactor to a weak alkaline pH of 8-9, heat to 60°C and keep warm for 1 hour.

The remaining conditions are the same as those in Example 1.

The data records of the acetonitrile recovery rate, the yield of the intermediate product N-p-chlorobenzyl trifluoroacetamide and the yield of the final product 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile in Example 1, Example 2, Comparative Example 1 and Comparative Example 2 are shown in the following table:

The data records of the acetonitrile recovery rate, the yield of the intermediate product N-p-chlorobenzyl trifluoroacetamide and the yield of the final product 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile in Example 1 and Example 3-10 are shown in the following table:

The data records of the yield of the intermediate product N-p-chlorobenzyl trifluoroacetamide and the yield of the final product 2-p-chlorophenyl-5-(trifluoromethyl)pyrrole-3-carbonitrile in Example 2, Example 11 and Example 12 are shown in the following table:

According to the embodiments of the present invention as described above, these embodiments do not describe all the details in detail, nor do they limit the invention to specific embodiments. Obviously, many modifications and changes can be made based on the above description. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can make good use of the present invention and the modified use based on the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A process for the preparation of 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile, comprising the steps of:

S1, sequentially adding p-chlorophenylglycine, trifluoroacetic acid and acetonitrile into a reaction kettle, adding a catalyst into the reaction kettle, uniformly stirring, heating, dripping a mixed liquid of solid phosgene and acetonitrile into the reaction kettle, and preserving heat;

s2, heating, namely dripping the mixed solution of the solid phosgene and the acetonitrile into the reaction kettle again, and preserving heat;

S3, sampling and detecting, namely reducing the pressure in the reaction kettle after the reaction is finished, recovering acetonitrile to obtain N-p-chlorobenzyl trifluoroacetamide, and weighing and metering;

S4, adding N-p-chlorobenzyl trifluoroacetamide into a reaction kettle, sequentially adding DMF and 2-chloroacrylonitrile, adding an additive to adjust the internal environment of the reaction kettle to be slightly alkaline, heating, and preserving heat;

s5, cooling, crystallizing and filtering to obtain 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-nitrile, and weighing and metering.

2. The process for preparing 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile according to claim 1, wherein:

in S1, the heating temperature is 50-55 ℃, the dripping time of the mixed liquid is 6 hours, and the heat preservation time is 2 hours.

3. The process for preparing 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile according to claim 2, wherein:

In S1, the mass ratio of the solid phosgene to the acetonitrile in the mixed solution is 18:20-30, and the mass ratio of the p-chlorophenylglycine, the trifluoroacetic acid and the acetonitrile is 25:23:65-85.

4. A process for the preparation of 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile according to claim 3, wherein:

In S1, the catalyst is phosphorus trichloride or phosphorus oxychloride, and the p-chlorophenylglycine can be replaced by p-chlorophenylglycine sodium salt.

5. The process for preparing 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile according to claim 1, wherein:

S2, heating at 65-80 ℃, dripping mixed liquid for 3 hours, and preserving heat for 0.5-2 hours.

6. The process for preparing 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile according to claim 5, wherein:

in S2, the mass ratio of the solid phosgene to the acetonitrile in the mixed solution is 17:22-28.

7. The process for preparing 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile according to claim 1, wherein:

In S4, the temperature of DMF before being added into the reaction kettle is lower than 5 ℃, the temperature of 2-chloroacrylonitrile before being added into the reaction kettle is 20-25 ℃, the heating temperature is 45-65 ℃, and the heat preservation time is 0.5-2 hours.

8. The process for preparing 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile according to claim 7, wherein:

In S4, the mass ratio of DMF to 2-chloroacrylonitrile is 21-26:3.

9. The process for preparing 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile according to claim 8, wherein:

in S4, the additive is ammonia or triethylamine, and the weak alkaline environment is pH 8-9.

10. The process for preparing 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile according to claim 1, wherein:

the mass ratio of the p-chlorophenylglycine to the 2-chloroacrylonitrile is 25:12.