2-Methyltetrahydrofuran → (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde

Temperatur

95 °C

A round-bottom flask equipped with a magnetic stir bar, a reflux condenser, internal thermometer, and a N2 inlet was charged with 5-(but-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (50.0 g, 197 mmol; Intermediate 3), bis(pinacolato)diboron (50.4 g, 199 mmol), and anhydrous 2-methyltetrahydrofuran (393 mL) followed by Pt(PPh3)4 (1.83 g, 1.5 mmol). This mixture was degassed with three vacuum/N2 cycles, heated at 83° C. (internal temperature; oil bath at 95° C.) for 5 h under N2, and then allowed to cool to room temperature. 2-Methyltetrahydrofuran (393 mL), cesium carbonate (128.1 g, 393 mmol), and water (11.8 mL, 1.5% v/v) were added, and the reaction was cooled to 4° C. 4-Iodobenzaldehyde (45.6 g, 197 mmol) and PdCl2(PPh3)2 (6.90 g, 9.8 mmol) were added, and the reaction was degassed with three vacuum/N2 cycles. The mixture was allowed to warm to room temperature and stirred overnight. Aqueous KOH solution (4M, 275 mL, 1100 mmol) and 2-chloro-4-fluoroiodobenzene (70.6 g, 275 mmol) were added. The reaction was degassed with 3 vacuum/N2 cycles, heated at 75° C. (internal temperature; oil bath at 90° C.) for 7 h under N2, and then allowed to cool to room temperature. The layers were separated, and the organic layer was washed with brine (800 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give the title compound (82.6 g, 7:1 mixture of regioisomers) as a pale yellow foam. Data for major isomer; (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde: 1H NMR (300 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.15 (s, 1H), 7.78-7.71 (m, 2H), 7.61 (d, 2H), 7.43-7.27 (m, 3H), 7.15 (m, 3H), 5.86 (dd, 1H), 3.93-3.85 (m, 1H), 3.79-3.68 (m, 1H), 2.44-2.36 (m, 3H), 2.10-1.96 (m, 2H), 1.81-1.67 (m, 1H), 1.63-1.53 (m, 2H), 0.92 (t, 3H);

1. customA round-bottom flask equipped with a magnetic stir bar, a reflux condenser
2. customThis mixture was degassed with three vacuum/N2 cycles
3. temperatureto cool to room temperature
4. temperaturethe reaction was cooled to 4° C
5. customthe reaction was degassed with three vacuum/N2 cycles
6. temperatureto warm to room temperature
7. customThe reaction was degassed with 3 vacuum/N2 cycles
8. temperatureheated at 75° C. (internal temperature; oil bath at 90° C.) for 7 h under N2
9. temperatureto cool to room temperature
10. customThe layers were separated
11. washthe organic layer was washed with brine (800 mL)
12. dry with materialdried over sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated
15. customThe crude product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes)

ORD-Eintrag

ord-cdea740ebefa4b72b172ab68d66c662b

Quelldatensatz

uspto-grants-2013_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08455534B2