[Synthesis]
To a stirred solution of 2,4-dichloropyrimidine (3.00 g, 20.1 mmol) in toluene (25 mL) were sequentially added 4-fluorophenylboronic acid (2.82 g, 20.1 mmol), potassium carbonate (8.32 g, 60.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.630 g, 0.545 mmol), and a 1:1 (v/v) ethanol/water solvent mixture (36 mL). The reaction mixture was heated and stirred at 55 °C for 12 h and subsequently concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate as eluent to afford 2-chloro-4-(4-fluorophenyl)pyrimidine as a yellow solid (2.50 g, 61% yield).
The above product (1.27 g, 6.09 mmol) was dissolved in N,N-dimethylformamide (8 mL) and ethyl piperidine-4-carboxylate (0.959 g, 6.10 mmol) and cesium carbonate (2.10 g, 6.44 mmol) were added. The reaction mixture was heated and stirred at 100 °C for 12 h and subsequently concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate as eluent to afford ethyl 1-(4'-fluoro-[1,1'-biphenyl]-3-yl)piperidine-4-carboxylate as a yellow oil (1.60 g, 80% yield).
The above intermediate (1.60 g, 4.80 mmol) was dissolved in a 1:1 (v/v) methanol/water solvent mixture (20 mL) and solid sodium hydroxide (0.968 g, 24.2 mmol) was added. The reaction was concentrated under reduced pressure after 2 hours. The residue was dissolved in water and the pH was adjusted to about 6 with 1N hydrochloric acid and subsequently extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(4'-fluoro-[1,1'-biphenyl]-3-yl)piperidine-4-carboxylic acid as a white solid (1.40 g, 97% yield).
Using General Method D, the above carboxylic acid was subjected to an amide coupling reaction with Intermediate 5, resulting in 2-chloro-4-(4-fluorophenyl)-pyrimidine as a white solid (0.118 g, 27% yield).
1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 5.0 Hz, 1H), 8.07-8.04 (m, 2H), 7.15 (t, J = 9.0 Hz, 2H), 6.89 (d, J = 10.0 Hz, 1H), 5.38 (s, 1H), 4.97-4.95 (m, 2H), 3.02-2.83 (m, 8H), 2.39-2.37 (m, 2H), 1.96-1.51 (m, 13H) ppm.
13C NMR (100 MHz, CDCl3) δ 174.1, 165.3, 163.3, 163.2, 161.7, 158.4, 133.8, 129.0, 128.9, 115.7, 115.5, 105.2, 59.4, 53.1, 47.6, 46.1, 44.6, 43.5, 39.3, 36.1, 28.9, 39.3, 36.1, 28.9, 39.3 36.1, 28.9, 28.7, 25.1, 24.3, 24.2 ppm.
Purity: >96% (214 and 254 nm) LCMS; retention time: 1.44 min; (M+H+) 438.3. |