Sodium hydride → 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-6-(3-(methylsulfonyl)propoxy)pyrrolo[2,1-f][1,2,4]triazine

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Reaction Conditions

Reaction Steps

A mixture of 6-(3-methanesulfonyl-propoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol (620 mg, 2.17 mmol) and POCl3 (10 mL) was heated at 85° C. for 3 h. POCl3 was removed in vacuo to give a yellow solid, which was dissolved in dichloromethane, and washed successively with cold NaHCO3 solution and brine. The organics were dried, filtered and concentrated to afford the crude chloroimidate intermediate (610 mg), which was added to a pre-mixed solution of 4-fluoro-2-methyl-1H-indol-5-ol (664 mg, 4.02 mmol) and NaH (60% in mineral oil, 160 mg, 4.02 mmol) in DMF at 0° C. The resulting mixture was stirred at RT for 30 min, and diluted with dichloromethane, washed with 10% LiCl aqueous solution, dried concentrated. The residue was purified by flash column chromatography (silica gel, eluting from 10% ethyl acetate/dichloromethane to 30% ethyl acetate/dichloromethane). The desired fractions were combined and concentrated in vacuo to give a solid, which was washed with MeOH to afford the title compound as a white solid (610 mg, 65% yield). HRMS (M+H)+ Calcd. For C20H21FN4O4S: 432.12675. Found: 433.1329. 1H NMR (d-DMSO) δ 11.36 (br, 1H), 7.94 (s, 1H), 7.93 (s, 1H), 7.15 (d, 1H, J=8.4 Hz), 6.99 (m, 1H), 6.24 (s, 1H), 4.16 (t, 2H, J=6.16 Hz), 3.31 (t, 2H, J=5.7 Hz), 3.05 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H), 2.50 (m, 2H). Anal. Calcd. For C20H21FN4O4S: 0.4H2O: C, 54.58; H, 4.84; N, 12.56; S 7.29. Found: C, 54.61; H, 4.92; N, 12.65; S 7.33.

Provenance & Evidence