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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 1163070
Notes
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Reaction equation

HRID 1163070 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
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

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-6-yloxy)-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: 1.0H2O: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-f50556eb89cb4d0ca4875c6bc7b39e7d
Source dataset
uspto-grants-2010_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07820814B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes