Phosphorus oxychloride → 2-Phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid ethyl ester

2-Phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid was prepared according to the procedure described in Bioorg. Med. Chem. Lett. 2003, 13, 1517. A solution of 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (436 mg, 2 mmol) and benzamide (484 mg, 4 mmol) in ethanol (6 mL) in a sealed tube was heated at 120 degrees for 30 h. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography (silica gel 60, 230-400 mesh, 0-80% ethyl acetate in hexane for 25 min) to give 4-hydroxy-2-phenyl-4-trifluoromethyl-4,5-dihydro-oxazole-5-carboxylic acid ethyl ester as an off-white solid (229 mg, 38% yield). LCMS calcd for C13H12F3NO4 (m/e) 303, obsd 304 (M+H). The ester was dehydrated by heating with 2 mL of phosphorus oxychloride at 80 degree overnight. The reaction mixture was cooled and concentrated. The resulting residue was mixed with THF and concentrated again to remove remaining POCl3. The oily residue was quenched with water and extracted with DCM (2×). The organic layer was concentrated. The crude product was purified by flash chromatography (silica gel 60, 230-400 mesh, 0-50% ethyl acetate in hexane for 25 min) to yield 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid ethyl ester as an off-white solid (160 mg, 75% yield). The ester was hydrolyzed by stirring with lithium hydroxide monohydrate in a mixed solvent of 3:1:1 of THF:MeOH:water (3 mL) at RT for 4 h. The reaction was concentrated and water was added. The pH of the solution was adjusted to ˜1-2 with 1 N HCl. The white precipitate was collected by centrifugation and washed with water. After drying under vacuum, 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid was obtained as a white solid (141 mg, 98% yield. LCMS calcd for C11H6F3NO3 (m/e) 257, obsd 258 (M+H).