CLIAMS:no claims ,TagSPECI:Field of the Invention
The present invention provides a process for the preparation of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole.
Background of the Invention
The N-substituted fluorine-containing pyrazole derivatives are valuable in the field of medicine and agricultural chemicals.
The EP Patent No. 0,888,291 B1 provides a process for the preparation of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole by reacting ethyl-2,3-dicyanopropionate in ethanol with 2,6-dichloro-4-trifluoromethylaniline and sodium nitrite to give ethyl-2,3-dicyano-2-[2,6-dichloro-4-trifluoromethylphenyl)azo]propionate. The ethyl-2,3-dicyano-2-[2,6-dichloro-4-trifluoromethylphenyl)azo]propionate is cyclized in the presence of ammonia to provide 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)pyrazole. The purification of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole involves evaporation of ethanol. The mass is taken in a mixture of toluene/ethyl acetate and the solution is washed with water followed by evaporation of toluene. The solution of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole is than purified by multiple crystallizations.
Such synthesis, with respect to what is known in the prior art, is apparently advantageous in that it requires few steps and reagents. However, use of multiple solvents and multiple crystallizations for purification result in poor yield and industrial non viability of such processes. While carrying out the due experimentation, the present inventors observed that iso-propanol as a solvent, instead of ethanol, for the reaction of ethyl-2,3-dicyanopropionate with 2,6-dichloro-4-trifluoromethylaniline and sodium nitrite to obtain 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole, obviates many unit operations like evaporation of solvent, exchange of solvent and multiple crystallizations for purification of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole. Further, the present inventors have found that the disadvantages associated with prior art can be overcome to obtain highly pure 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole.
Summary of the Invention
The present invention provides a process for the preparation of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole, comprising;
a) reacting 2,6-dichloro-4-trifluoromethylaniline with ethyl-2,3-dicyanopropionate in the presence of iso-propanol,
b) contacting the step a) product with base, and
c) isolating 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole from the reaction mixture.
The present invention further provides a process for preparation of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole having purity greater than 99.5%, comprising;
a) reacting 2,6-dichloro-4-trifluoromethylaniline with ethyl-2,3-dicyanopropionate,
b) contacting the step a) product with base, and
c) isolating 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole having purity greater than 99.5%.
The present invention further provides a process for the purification of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole, comprising;
a) contacting 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole in alcohol solvent with water,
b) filtering the step a) product,
c) washing step b) product with water to obtain 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole.
Detailed Description of the Invention
The present invention provides a process for the preparation of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole, comprising;
a) reacting 2,6-dichloro-4-trifluoromethylaniline with ethyl-2,3-dicyanopropionate in the presence of iso-propanol,
b) contacting the step a) product with base, and
c) isolating 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole from the reaction mixture.
The present invention further provides a process for preparation of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole having purity greater than 99.5%, comprising;
a) reacting 2,6-dichloro-4-trifluoromethylaniline with ethyl-2,3-dicyanopropionate,
b) contacting the step a) product with base, and
c) isolating 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole having purity greater than 99.5%.
The 2,6-dichloro-4-trifluoromethylaniline and ethyl-2,3-dicyanopropionate may be prepared by any method known in the art, for example, in EP Patent No. 0,888,291 B1. The reaction of 2,6-dichloro-4-trifluoromethylaniline with ethyl-2,3-dicyanopropionate in the presence of iso-propanol may take place in the presence of sulphuric acid and sodium nitrite. The reaction may take place at a temperature of about -10oC to about 10oC, for example, about -5oC to about 5oC for about 30 minutes to about 5 hours. The base involved in step b) may be selected from ammonia, methylamine, dimethylamine, trimethylamine, sodium hydroxide, potassium.hydroxides, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate and cesium bicarbonate or mixture thereof. The 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole is isolated from reaction mixture by precipitation, filtration, decantation and crystallization or mixture thereof.
The 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole obtained by present invention has a purity greater than 99.5%, preferably greater than 99.7%, more preferably greater than 99.8% by HPLC.
The present invention further provides a process for the purification of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole, comprising;
a) contacting 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole in alcohol solvent with water,
b) filtering the step a) product,
c) washing step b) product with water to obtain 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole.
The starting 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole may be prepared by any method known in the art or by method disclosed in present invention. The starting 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole has a purity of 98.57% by HPLC. The 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole having purity is contacted with alcohol solvent. The alcohol solvent may be selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and n-pentanol or mixture thereof. The mixture of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole with alcohol solvent is contacted with water. The contacting with water is carried out at a temperature of about -5oC to about 5oC to precipitate 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole. The 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole is filtered at a temperature of about -5oC to about 5oC. The 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole is washed with water. The 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole obtained by present invention has a purity greater than 99.5%, preferably greater than 99.7%, more preferably greater than 99.8% by HPLC.
The 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole is a very useful intermediate in the synthesis of fipronil and ethiprole. The fipronil and ethiprole compounds may be prepared by any method known in the art using 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole, wherein 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole is prepared as per present invention.
The high performance liquid chromatography (HPLC) is Agilent make, 1260 quaternary gradient with UV-Vis. @ 275nM detector.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example
Preparation of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole
Sulphuric acid (50%, 100 g), iso-propanol (100 g) and sodium nitrite (20 g in 55g of water) were taken together in a reaction vessel and the temperature of the mixture was maintained at -5oC to 0oC. The 2,6-dichloro-4-trifluoromethylaniline (50 g), ethyl-2,3-dicyanopropionate (38 g) and iso-propanol (100 g) were added to the reaction mixture at a temperature of -5oC to 0oC. The reaction was monitored for the absence of 2,6-dichloro-4-trifluoromethylaniline. The ammonia was purged into the reaction mixture and the pH was maintained at 9. The reaction mixture was stirred for 30 minutes and water (300 g) was added to the mixture at -5oC to 0oC. The product, so obtained, was filtered, washed with water (150 g) and dried to obtain title product.
Yield: 80%
Purity (by HPLC): 99.9%
Comparative example
Preparation of 5-amino-3-cyano-1-(2, 6-dichloro-4-trifluoromethyl-phenyl)pyrazole in ethanol
Sulphuric acid (50%, 100 g), ethanol (100 g) and sodium nitrite (20 g in 55g of water) were taken together in a reaction vessel and the temperature of the mixture was maintained at -5oC to 0oC. The 2,6-dichloro-4-trifluoromethylaniline (50 g), ethyl-2,3-dicyanopropionate (38 g) and ethanol (100 g) were added to the reaction mixture at a temperature of -5oC to 0oC. The reaction was monitored for the absence of 2,6-dichloro-4-trifluoromethylaniline. The ammonia was purged into the reaction mixture and the pH was maintained at 9. The reaction mixture was stirred for 30 minutes and water (300 g) was added to the mixture at -5oC to 0oC. The product, so obtained, was filtered, washed with water (150 g) to obtain title product.
Purity (by HPLC): 98.57%