反応 #1001979

反応方程式

6-(3-methanesulfonyl-propoxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-4-ol

POCl3

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

NaH

→

title compound

収率 65.0%

4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-(3-methanesulfonyl-propoxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine

収率 65.0%

溶媒

dichloromethane

dichloromethane

DMF

反応条件

後処理

1. 1
   その他POCl3 was removed in vacuo
2. 2
   その他to give a yellow solid, which
3. 3
   洗浄washed successively with cold NaHCO3 solution and brine
4. 4
   その他The organics were dried
5. 5
   ろ過filtered
6. 6
   濃縮concentrated
7. 7
   その他to afford the crude chloroimidate intermediate (610 mg), which
8. 8
   洗浄washed with 10% LiCl aqueous solution
9. 9
   その他dried
10. 10
    濃縮concentrated
11. 11
    その他The residue was purified by flash column chromatography (silica gel, eluting from 10% ethyl acetate/dichloromethane to 30% ethyl acetate/dichloromethane)
12. 12
    濃縮concentrated in vacuo
13. 13
    その他to give a solid, which
14. 14
    洗浄was washed with MeOH

実験手順

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; N, 12.65; S, 7.33.

出典