Methyl iodide → 4-fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridine

Temperature

65 °C

To a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (408 mg, 3.0 mmol), in THF (5 mL) sodium hydride (60% in oil, 120 mg, 3.0 mmol) was added in small portions. After 30 min, benzenesulfonyl chloride (0.42 mL, 3.3 mmol) was added and stirred at 23° C. for 21 h. Ethyl acetate was added (25 mL), the mixture was cooled at 0° C., neutralized with a solution of saturated ammonium chloride and layers were separated. The aqueous layer was extracted twice with ethyl acetate (2×25 mL), the organic layers were combined, washed with water (100 mL), brine (100 mL), dried, and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 25% ethyl acetate in hexane to give of 1-benzenesulfonyl-4-fluoro-1H-pyrrolo[2,3-b]pyridine (683 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ 8.40 (1H, dd, J=5.8, 7.8 Hz), 8.12 (2H, dd, J=1.0, 6.3 Hz), 7.98 (1H, d, J=4.3 Hz), 7.73 (1H, tt, J=1.3, 6.9 Hz), 7.63 (3H, t, J=7.3 Hz), 7.25 (1H, dd, J=5.6, 9.9 Hz), 6.93 (1H, d, J=4.1 Hz). LCMS m/z 277 (M+H+). B. To a solution of 1-benzenesulfonyl-4-fluoro-1H-pyrrolo[2,3-b]pyridine (683 mg, 2.47 mmol), in THF (12.0 mL) at −78° C., n-butyllithium solution (2.36M in hexanes, 2.30 mL, 5.44 mmol) was added dropwise. After 90 min, iodomethane (0.31 mL, 4.95 mmol) was added rapidly. After 15 min, a solution of saturated ammonium chloride was added and the mixture was allowed to reach RT. The solution was extracted with ethyl acetate (3×15 mL), combined organic layers were washed with water (30 mL), brine (30 mL), dried, and concentrated in vacuo. The crude material was placed in of THF (12 mL) and a solution tetrabutylammonium fluoride (1.0 M in THF, 3.7 mL, 3.7 mmol) was added. The mixture was heated at 65° C. for 16 h. The mixture was cooled RT, concentrated in vacuo and the residue was purified by preparative HPLC to yield 4-fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 10.70 (1H, s), 8.13 (1H, t, J=5.8 Hz), 6.77 (1H, dd, J=5.3, 9.6 Hz), 6.25 (1H, s) 2.51 (3H, s). LCMS; m/z 151 (M+H+). C. To a solution of 4-fluoro-2-methyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 2.0 mmol), in THF (6 mL), sodium hydride (60% in oil, 84 mg, 2.1 mmol) was added in small portions. After 30 min, chlorotriisopropylsilane (0.45 mL, 2.1 mmol) was added and the mixture was stirred at 65° C. for 16 h. Ethyl acetate was added (25 mL), the mixture was cooled at 0° C., neutralized with a solution of saturated ammonium chloride and layers were separated. The aqueous layer was extracted twice with ethyl acetate (2×25 mL), the organic layers were combined, washed with water (100 mL), brine (100 mL), and concentrated in vacuo. The crude material was purified by flash chromatography eluting with hexanes to give 4-fluoro-2-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (400 mg, 65%) as a colorless oil. LCMS; m/z 307 (M+H+).

1. waitAfter 15 min
2. customto reach RT
3. extractionThe solution was extracted with ethyl acetate (3×15 mL)
4. washwere washed with water (30 mL), brine (30 mL)
5. customdried
6. concentrationconcentrated in vacuo
7. temperatureThe mixture was cooled RT
8. concentrationconcentrated in vacuo
9. customthe residue was purified by preparative HPLC

ORD record

ord-9b142f549a3246f598318816f5987fe4

Source dataset

uspto-grants-2005_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06969717B2