Potassium Carbonate → N-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propyl)methanesulfonamide

HRID 2111780Notes

Reaction equation

HRID 2111780 reaction equation
[OH:1][C:2]1[C:7]2=[C:8]([CH3:20])[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)Cl.[F:26][C:27]1[C:35](O)=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([CH3:37])[NH:31]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[F:26][C:27]1[C:35]([O:1][C:2]2[C:7]3=[C:8]([CH3:20])[C:9]([O:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][N:6]3[N:5]=[CH:4][N:3]=2)=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([CH3:37])[NH:31]2

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 24813Phosphorus oxychlorideHCID 103520364-fluoro-2-methyl-1H-indol-5-olHCID 178431435HCID 178431435, compound

Product 1

HCID 11604763N-(3-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propyl)methanesulfonamideYield 36.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of N-[3-(4-hydroxy-5-methylpyrrolo[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. HRMS (M+H)+ Calcd. For C20H22FN5O4S: 447.1376. Found: 448.1476. 1H NMR (CDCl3) δ7.75 (s, 1H), 7.24 (s, 1H), 7.03 (d, 1H, J=8.32 Hz), 6.88 (m, 1H), 4.04 (t, 2H, J=5.72 Hz), 3.31 (t, 2H, J=6.16 Hz), 2.90 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H), 2.04 (m, 2H). Anal. Calcd. For C20H21FN4O4S:1.0 H2O:0.18 TFA: C, 50.57; H, 4.73; N 14.61; S 6.80. Found: C 50.44; H 4.87; N 14.51; S 6.70.

Workup

  1. customThe volatiles were removed
  2. additionthe residue was diluted with dichloromethane
  3. washwashed successively with cold NaHCO3 solution and brine
  4. customdried
  5. concentrationconcentrated in vacuo
  6. customto afford the crude chloroimidate intermediate (610 mg), which
  7. filtrationthe solid was filtered
  8. concentrationThe filtrate was concentrated
  9. customthe residue was purified by silica gel flash column chromatography
  10. washeluting with 30% ethyl acetate/dichloromethane
  11. customThe desired product was further purified by preparative HPLC

Sources & evidence

ORD record
ord-a613fbfba0d04c62871903b9524d739e
Source dataset
uspto-grants-2009_04
Patent number
US07521450B2

Reaction notes

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