Ethylenediamine → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)ethyl]-amide

HRID 246555Notes

Reaction equation

HRID 246555 reaction equation
[F:1][C:2]([F:42])([F:41])[C:3]1[NH:7][C:6]([C@@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])=[N:5][CH:4]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl.C(OCC)(=O)C.O>[F:42][C:2]([F:1])([F:41])[C:3]1[NH:7][C:6]([C@@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])=[N:5][CH:4]=1

Participants

7

Reactant 3

HCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 712858682-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)-ethyl]-amide

Product 1

HCID 712884652-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)ethyl]-amideYield 60.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)-ethyl]-amide (34 mg, 56.4 μmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (174 μL, 2.26 mmol) at 20° C. After 3 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated again. The residue was then suspended in dichloromethane (1 mL) and ethylenediamine (229 μL, 3.39 mmol) added. The mixture was stirred for 1 h, then diluted with ethyl acetate and water. The organic layer was washed with brine, then dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 12 g Analogix column, 0-10% methanol in dichloromethane, gradient over 30 min) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)ethyl]-amide (16 mg, 60%) as a light yellow solid. MS (M+H)+=473; 1H NMR (DMSO-d6) δ: 12.94 (d, J=3.0 Hz, 1H), 12.80 (br. s., 1H), 9.12 (s, 1H), 8.63 (d, J=8.5 Hz, 1H), 8.50 (d, J=3.3 Hz, 1H), 8.42-8.49 (m, 1H), 7.72 (s, 1H), 7.67 (dd, J=9.8, 2.0 Hz, 1H), 7.00 (td, J=9.2, 2.3 Hz, 1H), 5.32-5.59 (m, 1H), 4.14 (s, 3H), 1.64 (d, J=6.8 Hz, 3H).

Workup

  1. concentrationthe mixture was concentrated in vacuo
  2. additionThe residue was diluted with dichloromethane
  3. concentrationconcentrated again
  4. washThe organic layer was washed with brine
  5. dry with materialdried (sodium sulfate)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by chromatography (silica, 12 g Analogix column, 0-10% methanol in dichloromethane, gradient over 30 min)

Sources & evidence

ORD record
ord-dd3b77369b814321b7463f4a7b32eb76
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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