CN1218935C - Substituted benzoyl urea insect growth regulator synthesizing method - Google Patents

Abstract

The invention relates to a synthesis method of a substituted benzoylurea insect growth regulator, in particular to a synthesis method of hexaflumuron, fluflubenzuron and diflubenzuron. The method uses 2,6-difluorobenzonitrile as a starting material to obtain substituted benzoylurea compounds through fluorination, hydrolysis, esterification and addition. This method uses highly active potassium fluoride and quaternary ammonium salt catalysts in the fluorination step, which greatly shortens the fluorination reaction time; uses a base-catalyzed hydrolysis reaction in the hydrolysis step to reduce the special requirements for equipment; in the esterification step Use phosgene instead of oxalyl chloride to reduce the cost of esterification reaction; use a catalyst in the addition step to increase the yield of the addition reaction. The method has the advantages of high yield, simple steps, cheap raw materials, and is more suitable for industrial production scale. Using this method, the yield of diflubenzuron was 97%, that of hexaflumuron was 93%, and that of diflubenzuron was 86%.

Description

Synthesis method of substituted benzoyl urea insect growth regulator

Technical Field

The invention relates to a synthesis method of a substituted benzoyl urea insect growth regulator, in particular to a synthesis method of hexaflumuron, flufenoxuron and diflubenzuron.

Technical Field

Benzoylureas are a class of potent insecticidal and acaricidal agents that act by inhibiting the synthesis of insect chitin, otherwise known as insect growth regulators. Among them, hexaflumuron (hexaflumuron), flufenoxuron, diflubenzuron, etc. developed by DOW ELAN company in 1987 are the most common.

The synthesis of the compound mostly uses 2, 6-dichlorobenzonitrile as an initial raw material, and the substituted benzoyl urea compound is obtained by fluorination, hydrolytic esterification and addition, for example, the reaction formula is as follows:

1) fluorination:

2) hydrolysis:

3) esterification:

4) addition:

wherein,

the diflubenzuron synthesis described in Donbo et al, pesticide vol.39 No. 32000, was prepared as described above. However, the hydrolysis in the step 2) of the method adopts 90% concentrated sulfuric acid, so that the method has strict requirements on reaction equipment, needs acid-proof materials for preparation, and has high potential danger; the esterification in the step 3) uses oxalyl chloride, so that the cost is high; the obtained product needs to be separated and purified, and the steps are complicated.

For step 1), CN85100467A discloses a method for preparing fluorobenzonitrile from chlorobenzonitrile, which has improved yield (86% higher than the general method), but is still not very high; in addition, the perfluoroalkyl oxacarboxylic acid derivative is used as a catalyst in the method, and the preparation of the ring-opening ether catalyst is complicated, which is not beneficial to industrial production.

For step 3), vao-yonghua in the synthesis of hexaflumuron described in the pesticide vol.40 No. 112001, 2, 6-difluorobenzamide was esterified with oxalyl chloride, which is costly and the resulting iso-ester was not stable enough at room temperature, for which reason the authors tried to use cheap phosgene instead of oxalyl chloride, but the reaction was difficult to perform.

In the synthesis of the flufenoxuron described in the chemical reaction engineering and process vol.10 No. 11994.12, the esterification in the step 3) uses oxalyl chloride, so the cost is high; dichloromethane is used as a solvent, so that the obtained product, namely the isopropyl ester, is yellow oily matter and can be used in the next step only by further purification; and the yield was only 74%. In step 4), no catalyst is used, so that the reaction time is too long; and the same solvent is not used in the step 3) and the step 4), so that the process condition during industrial production is increased.

In summary, the prior art has the following disadvantages:

the fluorination in the step 1) is to use potassium fluoride obtained by calcination, no catalyst is added, the reaction time is as long as 20 hours, but the yield is as low as 50 percent; or perfluoroalkyl oxacarboxylic acid derivatives are used as the catalyst, and the preparation of the catalyst is complicated and is not beneficial to industrial production;

the hydrolysis in the step 2) adopts 90% concentrated sulfuric acid, so that the requirement on reaction equipment is strict, an acid-proof material is required to be prepared, and the potential danger is high;

the esterification in the step 3) usually uses oxalyl chloride, and has high cost which is 6 times that of phosgene; the obtained product needs to be separated and purified from the solution, and the steps are complicated;

the addition in the step 4) is carried out by adopting fluorobenzoyl isocyanate and substituted aniline under the condition of no catalyst, and the reaction yield is not high.

Disclosure of Invention

The invention aims to overcome the defects that in the prior art, when the substituted benzoyl urea insect growth regulator is synthesized, the fluorination reaction time is long, the yield is low, the hydrolysis reaction has special requirements on equipment due to the use of acid catalysis, the operation is dangerous, the esterification reaction cost is high, products need to be separated, and the addition reaction yield is not high enough, so that the invention provides the synthesis method of the substituted benzoyl urea insect growth regulator, which uses the potassium fluoride and the quaternary ammonium salt catalyst with high activity, greatly shortens the fluorination reaction time, uses the base to catalyze the hydrolysis reaction so as to reduce the special requirements on the equipment, uses phosgene to replace oxalyl chloride, reduces the esterification reaction cost, and uses the catalyst to improve the addition reaction yield.

The purpose of the invention is realized by the following technical scheme:

the invention provides a method for synthesizing a substituted benzoyl urea insect growth regulator, which comprises the following steps:

1) fluorination: heating a mixture of 1 mol of 2, 6-dichlorobenzonitrile, 1.5-2.0 mol of 450-mesh 550-mesh anhydrous potassium fluoride, a solvent and a catalyst A in a reaction kettle at 200 ℃ for 8-10 hours, filtering, fractionating the filtrate to obtain 2, 6-difluorobenzonitrile, and recovering the solvent;

the solvent is sulfolane;

the catalyst A is a mixture of tetrabutylammonium chloride and methyl trioctyl ammonium chloride, wherein the tetrabutylammonium chloride accounts for 40-60 wt%; the amount of the catalyst A is 1-3 wt% of the weight of the 2, 6-dichlorobenzonitrile;

2) hydrolysis: adding 1 mol of 2, 6-difluorobenzonitrile obtained in the step 1) and a catalyst B into a reaction kettle, dripping excessive hydrogen peroxide while stirring, keeping the reaction temperature at 40 ℃, keeping the temperature for 1 hour after finishing dripping, removing unreacted hydrogen peroxide under negative pressure, and spin-drying a reactant by a centrifuge to obtain a 2, 6-difluorobenzamide filter cake;

the catalyst B is one or two of sodium hydroxide, sodium carbonate or sodium bicarbonate in a weight ratio of 1: 1; the amount of the catalyst B is 1-3 wt% of the weight of the 2, 6-difluorobenzonitrile;

3) esterification: dissolving the 2, 6-difluorobenzamide filter cake obtained in the step 2) in a solvent, introducing excessive phosgene, and heating and refluxing for 4 hours to generate 2, 6-difluorobenzoyl isocyanate; the obtained product can be directly used in the next step without purification; the solvent is toluene;

4) addition: dissolving the 2, 6-difluorobenzoyl isocyanate obtained in the step 3) in toluene, adding equimolar substituted aniline and a catalyst C, and reacting at 100-110 ℃ for 4-6 hours to obtain a substituted benzoyl urea insect growth regulator;

the substituted aniline is 4-chloroaniline, 3, 5-dichloro-4- (1, 1, 2, 2-tetrafluoroethoxy) aniline or 4- (2-chloro-4-trifluoromethylphenoxy) -2-fluoroaniline;

the catalyst C is triethylamine or/and triethanolamine; the amount of the catalyst C is 1-3 wt% of the weight of the 2, 6-difluorobenzoyl isocyanate.

The reaction formula is as follows:

wherein,

compared with the prior art, the synthesis method provided by the invention has the advantages that:

1) the invention is different from the prior art, is realized in a laboratory, and is more suitable for industrial production scale;

2) in the fluorination step, quaternary ammonium salt is used as a catalyst, and fine anhydrous potassium fluoride is used, so that the yield of difluorobenzonitrile reaches up to 96%; the quaternary ammonium salt is a widely used phase transfer catalyst, is cheap and easy to obtain, and is easy for industrial production;

3) the hydrolysis step of the method adopts base catalysis, does not need acid-proof equipment, and keeps high yield of 92 percent;

4) in the esterification step, phosgene with low cost is adopted to replace oxalyl chloride, so that the cost is reduced, and the high yield is kept at 91%; moreover, the obtained product does not need to be purified and can be directly used for the next reaction;

5) the addition step of the invention uses the same solvent as the esterification step, thus simplifying the industrial operation; in addition, triethylamine or triethanolamine is used as a catalyst in the step, so that the yield of the reaction is improved, the yield of diflubenzuron is 97%, the yield of hexaflumuron is 93%, and the yield of flufenoxuron is 86%.

Detailed Description

Example 1

1) Fluorination: adding 500Kg of sulfolane into a 1000L reaction kettle, adding 88.4Kg (1.5 kmol) of fine-particle potassium fluoride (450 mesh) which is treated by spray drying, 172Kg (1 kmol) of 2, 6-dichlorobenzonitrile and 1.72Kg of a catalyst mixture consisting of 40 wt% of tetrabutylammonium chloride and 60 wt% of methyltrioctylammonium chloride while stirring, heating at 200 ℃ for 8 hours, filtering to remove precipitated potassium chloride, fractionating the filtrate to obtain 133.6Kg (0.96 kmol) of 2, 6-difluorobenzonitrile, yield of 96.1%, content of 98.4%, and recovering sulfolane as a solvent;

2) hydrolysis: adding 109.9Kg (0.79 kmol) of 2, 6-difluorobenzonitrile and 1.10Kg (1.7%) of sodium hydroxide serving as a catalyst into a reaction kettle, starting hot steam to heat up, dripping 72.63Kg (2.14 kmol) of hydrogen peroxide within 2 hours, keeping the temperature at 40 ℃ for 1 hour after finishing dripping, carrying out centrifugal drying on reactants by using a centrifugal machine to obtain 114.4Kg (0.728 kmol) of 2, 6-difluorobenzamide filter cake, wherein the yield is 92.2%, and the content is 98.7%;

3) esterification: adding 98Kg (0.62 kilomol) of 2, 6-difluorobenzamide filter cake and 417.2Kg of toluene into a reaction kettle, introducing 111.9Kg (1.13 kilomol) of phosgene, heating and refluxing for 4 hours to generate 103.0Kg (0.56 kilomol) of 2, 6-difluorobenzoyl isocyanate, wherein the yield is 90.9 percent, and the obtained product can be directly used in the next step without purification;

4) addition: 62.2Kg (0.34 kmol) of 2, 6-difluorobenzoyl isocyanate, 94.5Kg (0.34 kmol) of 3, 5-dichloro-4- (1, 1, 2, 2-tetrafluoroethoxy) aniline and 0.622Kg of triethylamine obtained in the above steps are dissolved in 500Kg of toluene to react at 100 ℃ for 6 hours, the reaction solution is centrifugally filtered, and the filter cake is collected and dried to obtain 144.7Kg (0.31 kmol) of hexaflumuron, with a yield of 92.3% and a content of 97.2%, and the filtrate is further concentrated to obtain 2.3Kg of hexaflumuron, which is calculated as 93.8%.

Example 2

1) Fluorination: adding 500Kg of sulfolane into a 1000L reactor, adding 117.8Kg (2 kmol) of fine-particle potassium fluoride (550 mesh) treated by spray drying, 172Kg (1 kmol) of 2, 6-dichlorobenzonitrile, and 5.16Kg of a catalyst mixture consisting of 60 wt% tetrabutylammonium chloride and 40 wt% methyltrioctylammonium chloride while stirring, heating at 200 ℃ for 10 hours, filtering to remove precipitated potassium chloride, fractionating the filtrate to obtain 134.1Kg (0.965 kmol) of 2, 6-difluorobenzonitrile in a yield of 96.5% and a content of 99.3%, and recovering sulfolane as a solvent;

2) hydrolysis: adding 109.9Kg (0.79 kmol) of difluorobenzonitrile, 1.10Kg (sodium hydroxide) of catalyst and 1.10Kg (sodium carbonate) of sodium hydroxide into a reaction kettle, starting hot steam to heat up, dropwise adding 51Kg (1.5 kmol) of hydrogen peroxide within 2 hours, keeping the temperature at 40 ℃ for 1 hour after the dropwise adding is finished, keeping the temperature for 1 hour under excessive negative pressure, and spin-drying the reactant by using a centrifugal machine to obtain 112.8Kg (0.718 kmol) of difluorobenzamide filter cake, wherein the yield is 90.9%, and the content is 98.5%;

3) esterification: adding 98Kg (0.62 kilomol) of 2, 6-difluorobenzamide filter cake and 417.2Kg of toluene into a reaction kettle, introducing 198.0Kg (1.2 kilomol) of phosgene, heating and refluxing for 4 hours to generate 104.1Kg (0.57 kilomol) of 2, 6-difluorobenzoyl isocyanate, wherein the yield is 91.8 percent, and the obtained product can be directly used in the next step without purification;

4) addition: 91.5Kg (0.5 kmol) of 2, 6-difluorobenzoyl isocyanate, 153Kg (0.5 kmol) of 4- (2-chloro-4-trifluoromethylphenoxy) -2-fluoroaniline and 1.83Kg of triethanolamine obtained in the previous step are dissolved in 500Kg of toluene, and reacted at 110 ℃ for 4 hours, the reaction solution is cooled to room temperature and filtered to obtain 209.8Kg (0.43 kmol) of colorless crystal flufenoxuron, the yield is 85.1%, the content is 99.0%, the filtrate is further concentrated, and 2.2Kg of flufenoxuron can also be obtained, and the calculated yield is 86.9%.

Example 3

1) Fluorination: adding 500Kg of sulfolane into a 1000L reactor, adding 106.0Kg (1.8 kmol) of fine potassium fluoride (500 mesh) which has been subjected to spray drying treatment, 172Kg (1 kmol) of 2, 6-dichlorobenzonitrile, and 3.44Kg of a catalyst mixture consisting of 50 wt% of tetrabutylammonium chloride and 50 wt% of methyltrioctylammonium chloride while stirring, heating at 200 ℃ for 9 hours, filtering to remove precipitated potassium chloride, fractionating the filtrate to obtain 133.7Kg (0.96 kmol) of 2, 6-difluorobenzonitrile, with a yield of 96.2%, a content of 98.8%, and recovering sulfolane as a solvent;

2) hydrolysis: adding 109.9Kg (0.79 kmol) of 2, 6-difluorobenzonitrile, 1.65Kg (sodium bicarbonate) of catalyst and 1.65Kg (sodium carbonate) of catalyst into a reaction kettle, starting hot steam to heat up, dropwise adding 102Kg (3.0 kmol) of hydrogen peroxide within 2 hours, after dropwise adding, keeping the temperature at 40 ℃ for 1 hour, keeping the temperature for excessive hydrogen peroxide under negative pressure, and centrifugally drying the reactant by using a centrifugal machine to obtain 115.1Kg (0.733 kmol) of 2, 6-difluorobenzamide filter cake, wherein the yield is 92.8 percent and the content is 98.8 percent;

3) esterification: 98Kg (0.62 kmol) of 2, 6-difluorobenzamide filter cake and 417.2Kg of toluene are added into a reaction kettle, 148.5Kg (1.51 kmol) of phosgene is introduced, and the mixture is heated and refluxed for 4 hours to generate 106.1Kg (0.58 kmol) of 2, 6-difluorobenzoyl isocyanate, wherein the yield is 93.5 percent, and the obtained product can be directly used in the next step without purification;

4) addition: 91.5Kg (0.5 kmol) of 2, 6-difluorobenzoyl isocyanate, 63.5Kg (0.5 kmol) of 4-chloroaniline and 1.37Kg of triethanolamine and 1.37Kg of triethylamine obtained in the above step are dissolved in 500Kg of toluene to react at 105 ℃ for 5 hours, the reaction solution is cooled to room temperature and filtered to obtain 148.8Kg (0.48 kmol) of white crystal diflubenzuron with a yield of 96.0% and a content of 98.0%, the filtrate is further concentrated to obtain 2.2Kg of diflubenzuron with a yield of 97.4%.

Claims (1)

1. A synthetic method of a substituted benzoyl urea insect growth regulator comprises the following steps:

1) fluorination: heating a mixture of 1 mol of 2, 6-dichlorobenzonitrile, 1.5-2.0 mol of 450-mesh 550-mesh anhydrous potassium fluoride, a solvent and a catalyst A in a reaction kettle at 200 ℃ for 8-10 hours, filtering, fractionating the filtrate to obtain 2, 6-difluorobenzonitrile, and recovering the solvent;

the solvent is sulfolane;

the catalyst A is a mixture of tetrabutylammonium chloride and methyl trioctyl ammonium chloride, wherein the tetrabutylammonium chloride accounts for 40-60 wt%; the amount of the catalyst A is 1-3 wt% of the weight of the 2, 6-dichlorobenzonitrile;

2) hydrolysis: adding 1 mol of 2, 6-difluorobenzonitrile obtained in the step 1) and a catalyst B into a reaction kettle, dripping excessive hydrogen peroxide while stirring, keeping the reaction temperature at 40 ℃, keeping the temperature for 1 hour after finishing dripping, removing unreacted hydrogen peroxide under negative pressure, and spin-drying a reactant by a centrifuge to obtain a 2, 6-difluorobenzamide filter cake;

the catalyst B is one or two of sodium hydroxide, sodium carbonate or sodium bicarbonate in a weight ratio of 1: 1; the amount of the catalyst B is 1-3 wt% of the weight of the 2, 6-difluorobenzonitrile;

3) esterification: dissolving the 2, 6-difluorobenzamide filter cake obtained in the step 2) in a solvent, introducing excessive phosgene, and heating and refluxing for 4 hours to generate 2, 6-difluorobenzoyl isocyanate; the obtained product can be directly used in the next step without purification;

the solvent is toluene;

4) addition: dissolving the 2, 6-difluorobenzoyl isocyanate obtained in the step 3) in toluene, adding equimolar substituted aniline and a catalyst C, and reacting at 100-110 ℃ for 4-6 hours to obtain a substituted benzoyl urea insect growth regulator;

the substituted aniline is 4-chloroaniline, 3, 5-dichloro-4- (1, 1, 2, 2-tetrafluoroethoxy) aniline or 4- (2-chloro-4-trifluoromethylphenoxy) -2-fluoroaniline;

the catalyst C is triethylamine or/and triethanolamine; the amount of the catalyst C is 1-3 wt% of the weight of the 2, 6-difluorobenzoyl isocyanate.