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With potassium carbonate; In dimethyl sulfoxide; acetone; at 20 - 55℃;Inert atmosphere; |
6-((6-(2-(2,4-difluorophenyl)-l,l-difluoro-2-hydroxy-3-(lH-tetrazol-l-yl)propyl)pyridin- 3-yl)methoxy)nicotinonitrile (98)To a magnetically stirred mixture of (6-((2-(2,4-difluorophenyl)oxiran-2- yl)difluoromethyl)pyridin-3-yl)methanol (BU from Example 53; 156 mg, 0.498 mmol) in Acetone (2.490 mL) was added K2C03 (138 mg, 0.996 mmol) in a dry 25 mL vial under N2 atmosphere. <strong>[3939-12-6]6-fluoronicotinonitrile</strong> (73.0 mg, 0.598 mmol) was added and the reaction mixture was stirred at RT for 2 hours, but no reaction progress was noted. DMSO (1 mL) was added, and the reaction mixture was stirred at RT overnight. HPLC-MS indicated the reaction was -50percent complete. The reaction mixture was heated to 55°C for 6 hours, at which point, TLC and HPLC-MS indicated the reaction was mostly complete. The crude material was diluted with ice-water and ether and the layers were separated. The aq. layer was extracted again with ether, and the combined ether extracts were dried over sodium sulfate, filtered, and evaporated. The crude residue was purified on silica (40 gram column, gradient to 20percent EA/Hex over 15 minutes, hold for 20 minutes) to afford compound BZ. Yield = 200 mg (92 percent) of a white waxy solid, .H NMR (400 MHz, CDCI3) delta 8.75 (s, 1H), 8.49 (dd, J = 2.4, 0.6 Hz, 1H), 7.84 (dd, J = 8.7, 2.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 14.7, 8.2 Hz, 1H), 6.91 (dd, J = 8.7, 0.6 Hz, 1H), 6.84 (ddd, J = 7.8, 2.4, 1.3 Hz, 1H), 6.78 - 6.70(m, 1H), 5.51 (s, 2H), 3.44 (d, J = 5.0 Hz, 1H), 3.01 - 2.94 (m, 1H). .H-decoupled NMR (376 MHz, CDCI3) delta -107.07 (d, J = 9.5 Hz), -107.54 (d, J = 9.5 Hz), -107.75 (d, J = 8.2 Hz), - 107.98 (d, J = 8.2 Hz), - 108.67 (d, J = 8.2 Hz), -109.35 (dd, J = 17.7, 9.5 Hz). MS (ESI): m/z 416.9 (M+H)+.To a magnetically stirred mixture of 6-((6-((2-(2,4-difluorophenyl)oxiran-2- yl)difluoromethyl)pyridin-3-yl)methoxy)nicotinonitrile (BZ; 200 mg, 0.482 mmol) and 1H- tetrazole (67.5 mg, 0.963 mmol) in dry DMF (4.815 mL) was added K2C03 (133 mg, 0.963 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at 55 °C for 36 hours, then cooled to RT, and diluted with ice-water and ether. The layers were separated and the aq. layer was extracted again with ether (2x). The combined ether extracts were dried over sodium sulfate, filtered, and evaporated. The crude residue was purified on silica (40 gram column, gradient over 15 min to 40percent EA/Hex, hold 10 min then 10 min at 80percent EA/hex, monitor 240 and 254 nm). The respective product fractions were evaporated to afford the title compound contaminated with DMF. The material was diluted with water and extracted 3x with ether, the combined ether extracts were diluted with pet. ether and washed with sat'd NH4CI (2x) and brine (lx), dried over MgS04, filtered, and evaporated to afford98. Yield = 62 mg (25.2 percent) of a white foam, .H NMR (400 MHz, CDCI3) delta 8.75 (s, 1H), 8.63 (d, J = 1.3 Hz, 1H), 8.48 (dd, J = 2.3, 0.8 Hz, 1H), 7.91 (dd, J = 8.2, 2.1 Hz, 1H), 7.85 (dd, J = 8.7, 2.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.35 (td, J = 9.0, 6.5 Hz, 1H), 6.92 (dd, J = 8.5, 0.8 Hz, 1H), 6.76 (ddd, J = 12.0, 8.5, 2.5 Hz, 1H), 6.71 - 6.61 (m, 1H), 5.56(d, J = 14.3 Hz, 1H), 5.50 (s, 2H), 5.13 (dd, J = 14.2, 1.1 Hz, 1H). .H-decoupled ^F NMR (376 MHz, CDCI3) delta -103.83 (ddd, J = 42.2, 17.0, 10.2 Hz), - 104.20 (d, J = 16.3 Hz), - 104.89 (d, J = 16.3 Hz), -107.90 - 108.07 (m), - 110.92 (dd, J = 262.9, 42.2 Hz). MS (ESI): m/z 486.1 (M+H)+. |
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