anitrazafen

Originator

Lilly 122512,Eli Lilly

Uses

Anti-inflammatory (topical).

Uses

Anitrazafen, is an effective antiinflammatory agent which has shown to have COX-2 inhibitor activity.

Manufacturing Process

Preparation of 5,6-bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine:
(A) 3-Hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine 2 moles, 540 g of anisil (4,4'-dimethoxybenzil), 222 g (2 moles) of semicarbazide hydrochloride, 180 g (2.2 moles) of sodium acetate, and 2.5 liters of acetic acid were heated at reflux overnight. The cooled reaction mixture was poured into 5 liters of water. The crude solid product was collected by filtration, washed with water, and recrystallized from acetic acid, giving 434 g of 3-hydroxy-5,6-bis(4- methoxyphenyl)-1,2,4-triazine; MP: about 272°-274°C.
(B) 3-Chloro-5,6-bis(4-methoxyphenyl)-1,2,4-triazine:
10 grams of 3-hydroxy-5,6-bis(4-methoxyphenyl)-1,2,4-triazine and 50 ml of phosphorous oxychloride were heated at reflux for 1.5 hours. The cooled mixture was poured onto crushed ice and the resultant mixture was extracted with diethyl ether. The extract was washed successively with 2% sodium hydroxide and water until the washings were neutral. The ether extract was dried over anhydrous sodium sulfate and evaporated. The residue was taken up in ether, filtered, and the filtrate was evaporated to yield 9.0 g of 3-chloro- 5,6-bis(4-methoxyphenyl)-1,2,4-triazine; MP: about 130°-132°C.
(C) 5,6-Bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine:
To a slurry of 11.7 g (0.33 mole) of methyltriphenylphosphonium bromide in 150 ml of dry tetrahydrofuran at -35°C was added, over a 15-minute period, 20 ml (0.033 mole) of n-butyl lithium. The reaction mixture was stirred for one hour. To the reaction mixture at -35° to -40°C was added over a 10- minute period a solution of 5.7 g (0.0165 mole) of 3-chloro-5,6-bis(4- methoxyphenyl)-1,2,4-triazine in 50 ml of tetrahydrofuran. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. A solution of 1.05 g (0.0165 mole) of sodium carbonate in 50 ml of water was added dropwise to the reaction mixture which then was heated at reflux for three hours. The reaction mixture was cooled, poured over ice, and extracted with diethyl ether. The diethyl ether extract was washed with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was chromatographed over silica gel, with three fractions being collected. After evaporation of solvent, the third fraction solidified; MP: about 109°-113°C. The solid was identified as 5,6-bis(4-methoxyphenyl)-3-methyl-1,2,4-triazine by nuclear magnetic resonance analysis, mass spectrographic analysis, and elemental microanalysis.

Therapeutic Function

Antiinflammatory

Raw materials

Preparation Products