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

HRID 984870ノート

反応式

HRID 984870 の反応式
[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]2[N:16]([CH:17]=1)[N:15]=[CH:14][N:13]=[C:12]2[OH:18])(=[O:4])=[O:3].O=P(Cl)(Cl)Cl.[F:25][C:26]1[C:34](O)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2.[H-].[Na+]>ClCCl.CN(C=O)C>[F:25][C:26]1[C:34]([O:18][C:12]2[C:11]3=[C:10]([CH3:19])[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:17][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2

参加物

7

反応物 4

HCID 24758Sodium hydrideHCID 24813Phosphorus oxychlorideHCID 103520364-fluoro-2-methyl-1H-indol-5-olHCID 178431468HCID 178431468、化合物

生成物 1

HCID 115029124-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-6-(3-(methylsulfonyl)propoxy)pyrrolo[2,1-f][1,2,4]triazine収率 65%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 6344Dichloromethane溶媒2 回

反応条件

温度
85 °C

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; H, 4.92; N, 12.65; S, 7.33.

後処理

  1. customPOCl3 was removed in vacuo
  2. customto give a yellow solid, which
  3. washwashed successively with cold NaHCO3 solution and brine
  4. customThe organics were dried
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto afford the crude chloroimidate intermediate (610 mg), which
  8. washwashed with 10% LiCl aqueous solution
  9. customdried
  10. concentrationconcentrated
  11. customThe residue was purified by flash column chromatography (silica gel, eluting from 10% ethyl acetate/dichloromethane to 30% ethyl acetate/dichloromethane)
  12. concentrationconcentrated in vacuo
  13. customto give a solid, which
  14. washwas washed with MeOH

出典と根拠

ORDレコード
ord-f50382a61dfe48289a5678ef1fd4b86b
出典データセット
uspto-grants-2005_03
特許番号
US06869952B2

反応ノート

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