General Steps:
Example C30. Synthesis of 4-trifluoromethyl-2-(4-trifluoromethylphenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid:
1) 5-Amino-1H-imidazole-4-carboxamide (25 g, 198 mmol) was dissolved in methanesulfonic acid (107 ml) and ethanol (400 ml) and stirred at reflux for 12 days. After completion of the reaction, the solvent was evaporated and water (300 ml) was added. The reaction was adjusted to pH=6 by slowly adding 32% sodium hydroxide solution under cooling in an ice water bath.The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3 x 200 ml). The organic layers were combined, dried with anhydrous magnesium sulfate, the solvent was evaporated, and the crude product was purified by crystallization (ethyl acetate/ethanol) to give ethyl 5-amino-1H-imidazole-4-carboxylate (13.7 g, 45%) as a light brown solid.MS (EI) 155.1 [M+]; m.p. 178 °C.
2) 4,4,4-Trifluoro-1-(4-trifluoromethylphenyl)-butane-1,3-dione (10.0 g, 35.2 mmol) was reacted with 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (5.0 g, 32.2 mmol) in acetic acid (120 ml) at reflux for 24 hours. After completion of the reaction, the solvent was evaporated and the crude product was purified by silica gel column chromatography (ethyl acetate/heptane) and crystallized (ethyl acetate/hexane) to afford ethyl 4-trifluoromethyl-2-(4-trifluoromethylphenyl)-imidazo[1,5-a]pyrimidine-8-carboxylate (5.65 g, 43%) as a yellow solid. mS (EI) 403.1 [M+]; m.p. 243 °C.
3) Ethyl 4-trifluoromethyl-2-(4-trifluoromethylphenyl)-imidazo[1,5-a]pyrimidine-8-carboxylate (5.6 g, 13.9 mmol) was dissolved in 2M potassium hydroxide solution (111 ml) and water (55 ml) and stirred at room temperature for 5 hours. The reaction solution was cooled in an ice water bath and acetic acid (30 ml) was added. The mixture was evaporated, acetic acid (150 ml) was added and heated at reflux for 20 minutes. The reaction mixture was evaporated, water (150 ml) was added and extracted with ethyl acetate (2 x 300 ml). The organic layers were combined, washed with brine (2 x 150 ml), dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified by silica gel column chromatography (ethyl acetate/heptane 1:1) to afford 4-trifluoromethyl-2-(4-trifluoromethylphenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (1.93 g, 37%) as a yellow solid.MS (ISN) 374.3 [M-H]-; m.p. 231 °C.
