General procedure for the synthesis of 4-chloro-2-(trifluoromethyl)pyrimidines from 2-(trifluoromethyl)pyrimidin-4-ol:
Intermediate 39a: potassium 2-[4-(trifluoromethyl)pyrimidin-2-yl]acetate [00458]
2-(Trifluoromethyl)-4-pyrimidinol (4.00 g, 24.38 mmol) was dissolved in phosphorochloridic acid (20 mL, 214.57 mmol) and a drop of N,N-dimethylformamide was added as a catalyst. The reaction mixture was heated to 120 °C and kept at this temperature for 2 hours. Upon completion of the reaction, the mixture was cooled to room temperature and subsequently concentrated under vacuum to remove the excess phosphoryl chloride. The residue was diluted with ethyl acetate (100 mL) and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography using a heptane solution of 50% ethyl acetate as eluent to give 4-chloro-2-(trifluoromethyl)pyrimidine (2.52 g, 13.8 mmol, 56% yield) as a light brown liquid.
1H NMR (DMSO-d6, 400MHz) δ/ppm: 9.07 (1H, d, J = 5.6Hz), 8.11 (1H, d, J = 5.6Hz).
MS Method 3: RT: 3.61 min, m/z 182.0 [M + H]+.
