Preparation method of flunixin

Abstract

The invention discloses a preparation method of flunixin. According to the invention, 2-methyl-3-trifluoromethylaniline and ethyl 2-chloro nicotinate are adopted as raw materials; polyethylene glycol or glycol is adopted as a solvent; and cuprous iodide and p-toluenesulfonic acid are adopted as catalysts. The materials are heated to a temperature of 80-100 DEG C, and are subject to a reaction under stirring; when the reaction is finished, an aqueous solution of alkali is added to the reaction product; the reaction product is hydrolyzed, and the pH of the product is regulated to a value below 5 by using an acid; the product is subject to pumping filtration, pressure reduction and drying, such that flunixin is obtained. The method provided by the invention is also advantaged in no requirement on vacuum distillation, and extremely low by-products. With the method provided by the invention, the yield of flunixin reaches approximately 90%, and the purity of flunixin is above 99%. The method is especially suitable for industrialized productions. With the method, the production cost can be reduced, and the yield can be improved.

Description

technical field

[0001] The invention relates to a preparation method of poultry medicine, in particular to a preparation method of flunixin, an intermediate of flunixin meglumine. Background technique

[0002] Flunixin meglumine is a special non-steroidal drug for animals. It mainly exerts antipyretic, anti-inflammatory and analgesic effects by inhibiting cyclooxygenase and reducing the production of inflammatory mediators such as prostaglandins. And flunixin is the key intermediate of flunixin meglumine. Because flunixin is mainly imported from abroad as a raw material, the preparation cost of flunixin meglumine prepared with flunixin is relatively high. For this reason, those skilled in the art try to provide a fluorine Nissin, to change the state of the art. At present, the obtained U.S. patent US5248781 discloses a preparation method of flunixin: 2-chloronicotinic acid ethyl ester and 2-methyl-3-trifluoromethylaniline are used as raw materials, and no solvent or xylen...

Examples

preparation example Construction

[0013] The preparation method of flunixin of the present invention adopts 2-methyl-3-trifluoromethylaniline and ethyl 2-chloronicotinate as raw materials, polyethylene glycol or ethylene glycol as solvent, cuprous iodide, Use p-toluenesulfonic acid as a catalyst, and react under heating to 80°C-100°C with stirring. After the reaction is completed, add an aqueous alkali solution, and after hydrolysis, use acid to adjust the pH value to less than 5, filter with suction, and wash the filter cake with ethanol. After washing, suction filtration, decompression, and drying, flunixin was obtained, wherein, the mixture of 2-methyl-3-trifluoromethylaniline and 2-chloronicotinic acid ethyl ester, cuprous iodide and p-toluenesulfonic acid The molar ratio is 1:1~1.5:0.001~0.005:0.001~0.005; the concentration of alkali aqueous solution is 10-50%; the mass volume ratio of 2-methyl-3-trifluoromethylaniline to solvent is 1:2~ 6; the reaction formula of the above-mentioned preparation method is...

Embodiment 1

[0017] Embodiment 1, a kind of preparation method of flunixin, concrete steps are as follows:

[0018] ①Put 300L polyethylene glycol into the reaction kettle, and at the same time, add 100kg of 2-methyl-3-trifluoromethylaniline, 106kg of ethyl 2-chloronicotinate, 0.2kg of cuprous iodide, p-methylbenzenesulfonate Put 0.18Kg of acid into the reaction kettle, heat to 85°C, react for 2 hours, and obtain a mixed solution after the reaction is completed;

[0019] ② Slowly add 500L 10% potassium hydroxide solution to the mixed solution in step ①, hydrolyze for 2 hours, and cool to room temperature after the reaction is completed;

[0020] ③ Use hydrochloric acid to adjust the liquid cooled to room temperature in step ②, to a pH value of 2, suction filter after stirring for 1 hour, and wash the filter cake twice with cold ethanol, each time the consumption of cold ethanol is 200L, after washing, suction filter, Dry under reduced pressure to obtain 152kg of flunixin with a yield of 90...

Embodiment 2

[0021] Embodiment 2, a kind of preparation method of flunixin, concrete steps are as follows:

[0022] ①Put 200L polyethylene glycol into the reaction kettle, and at the same time, add 100kg of 2-methyl-3-trifluoromethylaniline, 106.6kg of ethyl 2-chloronicotinate, 0.2kg of cuprous iodide, p-methylbenzene Put 0.18Kg of sulfonic acid into the reaction kettle, heat to 100°C, react for 2 hours, and obtain a mixed solution after the reaction is completed;

[0023] ② Slowly add 167L of 30% potassium hydroxide solution to the mixed solution in step ①, hydrolyze for 2 hours, and cool to room temperature after the reaction;

[0024] ③ Use hydrochloric acid to adjust the liquid cooled to room temperature in step ②, to a pH value of 3, suction filter after stirring for 1 hour, and wash the filter cake twice with cold ethanol, each time the consumption of cold ethanol is 200L, after washing, suction filter, Dry under reduced pressure to obtain 152kg of flunixin with a yield of 90%, whic...

technical field

[0001] The invention relates to a preparation method of poultry medicine, in particular to a preparation method of flunixin, an intermediate of flunixin meglumine. Background technique

[0002] Flunixin meglumine is a special non-steroidal drug for animals. It mainly exerts antipyretic, anti-inflammatory and analgesic effects by inhibiting cyclooxygenase and reducing the production of inflammatory mediators such as prostaglandins. And flunixin is the key intermediate of flunixin meglumine. Because flunixin is mainly imported from abroad as a raw material, the preparation cost of flunixin meglumine prepared with flunixin is relatively high. For this reason, those skilled in the art try to provide a fluorine Nissin, to change the state of the art. At present, the obtained U.S. patent US5248781 discloses a preparation method of flunixin: 2-chloronicotinic acid ethyl ester and 2-methyl-3-trifluoromethylaniline are used as raw materials, and no solvent or xylen...

Examples

preparation example Construction

[0013] The preparation method of flunixin of the present invention adopts 2-methyl-3-trifluoromethylaniline and ethyl 2-chloronicotinate as raw materials, polyethylene glycol or ethylene glycol as solvent, cuprous iodide, Use p-toluenesulfonic acid as a catalyst, and react under heating to 80°C-100°C with stirring. After the reaction is completed, add an aqueous alkali solution, and after hydrolysis, use acid to adjust the pH value to less than 5, filter with suction, and wash the filter cake with ethanol. After washing, suction filtration, decompression, and drying, flunixin was obtained, wherein, the mixture of 2-methyl-3-trifluoromethylaniline and 2-chloronicotinic acid ethyl ester, cuprous iodide and p-toluenesulfonic acid The molar ratio is 1:1~1.5:0.001~0.005:0.001~0.005; the concentration of alkali aqueous solution is 10-50%; the mass volume ratio of 2-methyl-3-trifluoromethylaniline to solvent is 1:2~ 6; the reaction formula of the above-mentioned preparation method is...

Embodiment 1

[0017] Embodiment 1, a kind of preparation method of flunixin, concrete steps are as follows:

[0018] ①Put 300L polyethylene glycol into the reaction kettle, and at the same time, add 100kg of 2-methyl-3-trifluoromethylaniline, 106kg of ethyl 2-chloronicotinate, 0.2kg of cuprous iodide, p-methylbenzenesulfonate Put 0.18Kg of acid into the reaction kettle, heat to 85°C, react for 2 hours, and obtain a mixed solution after the reaction is completed;

[0019] ② Slowly add 500L 10% potassium hydroxide solution to the mixed solution in step ①, hydrolyze for 2 hours, and cool to room temperature after the reaction is completed;

[0020] ③ Use hydrochloric acid to adjust the liquid cooled to room temperature in step ②, to a pH value of 2, suction filter after stirring for 1 hour, and wash the filter cake twice with cold ethanol, each time the consumption of cold ethanol is 200L, after washing, suction filter, Dry under reduced pressure to obtain 152kg of flunixin with a yield of 90...

Embodiment 2

[0021] Embodiment 2, a kind of preparation method of flunixin, concrete steps are as follows:

[0022] ①Put 200L polyethylene glycol into the reaction kettle, and at the same time, add 100kg of 2-methyl-3-trifluoromethylaniline, 106.6kg of ethyl 2-chloronicotinate, 0.2kg of cuprous iodide, p-methylbenzene Put 0.18Kg of sulfonic acid into the reaction kettle, heat to 100°C, react for 2 hours, and obtain a mixed solution after the reaction is completed;

[0023] ② Slowly add 167L of 30% potassium hydroxide solution to the mixed solution in step ①, hydrolyze for 2 hours, and cool to room temperature after the reaction;

[0024] ③ Use hydrochloric acid to adjust the liquid cooled to room temperature in step ②, to a pH value of 3, suction filter after stirring for 1 hour, and wash the filter cake twice with cold ethanol, each time the consumption of cold ethanol is 200L, after washing, suction filter, Dry under reduced pressure to obtain 152kg of flunixin with a yield of 90%, whic...