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 1163067Notes

Reaction equation

HRID 1163067 reaction equation
[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

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 24813Phosphorus oxychlorideHCID 103520364-fluoro-2-methyl-1H-indol-5-olHCID 178431468HCID 178431468, compound

Product 1

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

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
85 °C

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-3256259f032241cebf1bce72b19af2d7
Source dataset
uspto-grants-2010_10
Patent number
US07820814B2

Reaction notes

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