反应详情

温度

-78 °C

The azaindole intermediate 4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol was prepared as follows. E. 1H-Pyrrolo[2,3-b]pyridine-7-oxide (50 g, 1 eq.) and tetramethylammonium bromide (86 g, 1.5 eq.) were placed in DMF (500 mL). The mixture was cooled to 0° C. and methanesulfonic anhydride (130 g, 2 eq.) was added in small portions. The suspension was allowed to reach 23° C. and stirred for 4 h. The mixture was poured in water (1L) and the solution was neutralized with an aqueous solution of 50% sodium hydroxide (pH=7). Water (2L) was added and the mixture was cooled to 10° C. for 30 min. The solid formed was filtered and washed with cooled water (1L). The solid was dissolved in a mixture of dichloromethane/methanol (4:1), dried over MgSO4, concentrated in vacuo to afford 4-bromo-1H-pyrrolo[2,3-b]pyridine (40 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ 12.05 (1H, br. s), 8.08 (1H, d, J=5.3 Hz), 7.59 (1H, m), 7.33 (1H, d, J=5.05 Hz), 6.41 (1H, d, J=3.5 Hz). LCMS; m/z 197 (M+H)+. F. A 500-mL oven-dried flask capped with a rubber septum was evacuated and backfilled with argon. The flask was charged with 4-bromo-1H-pyrrolo [2,3-b]pyridine (40 g, 1 eq.) and THF (400 mL). The mixture was cooled to 0° C. and sodium hydride (60% in oil, washed with hexanes, 8.9 g, 1 eq) was added in small portions. After 15 min, chloro-triisopropylsilane (443.4 mL, 1 eq) was added, the tube was sealed and stirred at 80° C. for 3 h. The reaction mixture was cooled down, neutralized with saturated ammonium chloride (50 mL) and extracted twice with hexanes (2×800 mL). Combined organic layers were dried, and concentrated in vacuo to afford 4-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (71.1 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 8.09 (1H, d, J=5.1 Hz), 7.60 (1H, d, J=3.5 Hz), 7.37 (1H, d, J=5.3 Hz), 6.59 (1H, d, J=3.5 Hz), 1.85 (3H, septu. J=7.6 Hz), 1.04 (9H, d, J=7.6 Hz). LCMS; m/z 353 (M+H+). G. An 250 mL oven-dried round-bottom flask was evacuated and backfilled with Argon. The flask was charged 4-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (1.4 g, 1 eq), THF (25 mL) and the mixture was cooled to −78° C. Tert-butyllithium (1.7 M in pentane, 4.66 mL, 2 eq.) was added dropwise and after 5 minutes, N-fluorobenzenesulfonimide (1.25 g, 1 eq.) was added. After 45 min, a solution of saturated ammonium chloride (20 mL) was added and the mixture was allowed to reach RT. Water was added (40 mL) and the solution was extracted with hexanes (3×100 mL), combined organic layers were washed with water, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography eluting a mixture of 100% hexanes to give 4-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (970 mg, 84%). H. Procedures described in Example 4E and 4F were then followed to obtain the title compound.

1. customAn 250 mL oven-dried round-bottom flask was evacuated
2. customto reach RT
3. extractionthe solution was extracted with hexanes (3×100 mL)
4. washwere washed with water
5. dry with materialdried over MgSO4
6. concentrationconcentrated in vacuo
7. customThe crude material was purified by flash chromatography
8. washeluting
9. additiona mixture of 100% hexanes