Preparation of Flunisin Meglumine
Flunisin meglumine is a veterinary anti-inflammatory and analgesic drug with antipyretic, anti-inflammatory, and analgesic effects. It can significantly improve clinical symptoms and enhance the activity of antibiotics alone or in combination with antibiotics. Veterinary medicine is commonly used in clinical practice to alleviate pain and anti-inflammatory effects caused by internal colic, muscle and bone disorders in horses; The control of acute inflammation caused by various diseases of cattle, such as hoof leaf inflammation, arthritis, etc., can also be used as an auxiliary treatment for sow mastitis, endometritis, and lactation syndrome.
Preparation of flunicin:
(1) Add 500g of purified water, 55.1g of 2-chloronicotinic acid, 122.6g of 2-methyl-3-trifluoromethylaniline, 0.6g of p-toluenesulfonic acid, and 0.28g of copper oxide to a 1000mL reaction flask equipped with a reflux tube. Stir and raise the temperature until reflux, and incubate the reaction for 4 hours.
(2) Lower the temperature of the reaction solution to below 50 ℃, add 25% potassium hydroxide solution dropwise to the reaction solution, adjust the pH value to 10.0-11.0, continue stirring and cooling to below 20 ℃ after adjustment, stir thoroughly for 1 hour, and filter. The filter cake is mainly an excess of 2-methyl-3-trifluoromethylaniline, which can be recycled and reused.
(3) Drip 30% sulfuric acid into the filtrate to adjust the pH value to 5.0-6.0. Stir thoroughly for crystallization for 1 hour, filter, and wash the filter cake with 300g of purified water for 30 minutes. Filter and dry. 94.5g of product was obtained with a yield of 91% and HPLC purity of 99.1%.
Preparation of flunixin meglumine:
(1) Add 680mL of acetonitrile, 90g of flunicin, and 71.6g of meglumine to a 1000mL reaction flask equipped with a reflux tube, stir and raise the temperature to 75 ℃, clarify the reaction solution, and continue stirring for 2 hours.
(2) Heat filtration, temperature control not less than 70 ℃, use a fully preheated filter to filter the reaction solution while it is hot, remove the insoluble substances in the system, pour the filtrate back into the reaction bottle, start to stand, naturally cool down, precipitate crystals, start stirring, reduce to 20 ℃, incubate for 1 hour, filter, wash with acetonitrile, and dry to obtain 138.8g of flunicin meglumine, with a yield of 93% and HPLC greater than 99.9%. The product quality meets the requirements of EP7.5.
The preparation method of fluoronisin meglumine includes the following steps:
(1) Add 2-chloronicotinic acid and 2-methyl-3-trifluoromethylaniline to a sodium hydroxide aqueous solution and stir. The molar ratio of 2-chloronicotinic acid to 2-methyl-3-trifluoromethylaniline is 3:1; The molar ratio of 2-chloronicotinic acid to sodium hydroxide used for preparing sodium hydroxide aqueous solution is 1:2; Add ethylene glycol, chain polyethylene glycol dialkyl ether, and catalyst A, with the dosage of chain polyethylene glycol dialkyl ether being 3% of the mass of 2-chloronicotinic acid feed; The catalyst A is p-toluenesulfonic acid and copper oxide, with a molar ratio of 3:1; Control the temperature at 45 ℃, react for 0.6 hours, adjust the PH of the solution, leave it still for layering after stirring, filter after stirring, wash the filter cake, and dry it to obtain flunixine;
(2) React the obtained flunicin in step (1) with N-methylglucosamine in isopropanol, and the molar ratio of flunicin to N-methylglucosamine is 2:1; The ratio of the mass of flunixin to the volume of isopropanol is 1:11; Simultaneously add maltodextrin; The molar ratio of maltodextrin to 2-methyl-3-trifluoromethylaniline is 1:2.5; Heat reflux, filter, cool down, stir and crystallize. Wait until the system temperature drops below 25 ℃ and continue stirring. The crystals are filtered and washed with isopropanol to obtain flunixin meglumine.
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