4-fluoro-2-methyl-1H-indol-5-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1 g) was dissolved in a solution of potassium carbonate (1.3 g) in water (13 ml). A solution of sodium dithionite (5.24 g) in water (12.3 ml) was added dropwise. The mixture was stirred for 1.5 hours, then left to stand overnight. The solid was filtered and washed with water (6 ml). The solid was dried at 35° C. in a vacuum oven to give crude 4-fluoro-2-methyl-1H-indol-5-ol (0.5 g, 64.5%). left to stand overnight The solid was filtered washed with water (6 ml) The solid was dried at 35° C. in a vacuum oven

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-[3-(4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6yloxy)-propyl]-methanesulfonamide (530 mg, 1.77 mmol) and POCl3 was heated at 80° C. for 1.5 h. The volatiles were removed and the residue was diluted with dichloromethane, washed successively with cold NaHCO3 solution and brine, dried, and concentrated in vacuo to afford the crude chloroimidate intermediate (610 mg), which was heated with 4-fluoro-2-methyl-1H-indol-5-ol (495 mg, 3.0 mmol) and K2CO3 (3.0 g, 22 mmol) in DMF (8 mL) at 80-85° C. for 2 h. The mixture was diluted with dichloromethane and the solid was filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography eluting with 30% ethyl acetate/dichloromethane. The desired product was further purified by preparative HPLC to afford the title compound (290 mg, 34% yield) as a tan solid. The volatiles were removed the residue was diluted with dichloromethane washed successively with cold NaHCO3 solution and brine dried concentrated in vacuo to afford the crude chloroimidate intermediate (610 mg), which the solid was filtered The filtrate was concentrated the residue was purified by silica gel flash column chromatography eluting with 30% ethyl acetate/dichloromethane The desired product was further purified by preparative HPLC

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-[3-(4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6yloxy)-propyl]-methanesulfonamide (530 mg, 1.77 mmol) and POCl3 was heated at 80° C. for 1.5 h. The volatiles were removed and the residue was diluted with dichloromethane, washed successively with cold NaHCO3 solution and brine, dried, and concentrated in vacuo to afford the crude chloroimidate intermediate (610 mg), which was heated with 4-fluoro-2-methyl-1H-indol-5-ol (495 mg, 3.0 mmol) and K2CO3 (3.0 g, 22 mmol) in DMF (8 mL) at 80-85° C. for 2 h. The mixture was diluted with dichloromethane and the solid was filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography eluting with 30% ethyl acetate/dichloromethane. The desired product was further purified by preparative HPLC to afford the title compound (290 mg, 34% yield) as a tan solid. The volatiles were removed the residue was diluted with dichloromethane washed successively with cold NaHCO3 solution and brine dried concentrated in vacuo to afford the crude chloroimidate intermediate (610 mg), which the solid was filtered The filtrate was concentrated the residue was purified by silica gel flash column chromatography eluting with 30% ethyl acetate/dichloromethane The desired product was further purified by preparative HPLC

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-(3-methanesulfonyl-propoxy)-5-methyl-pyrrolo[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: 0.4 H2O: 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. POCl3 was removed in vacuo to give a yellow solid, which washed successively with cold NaHCO3 solution and brine The organics were dried filtered concentrated to afford the crude chloroimidate intermediate (610 mg), which 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) concentrated in vacuo to give a solid, which was washed with MeOH