Diisopropylethylamine → 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

HRID 246554

Reaction equation

HRID 246554 reaction equation
[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:44])([F:43])[C:35]1[NH:39][C:38]([C@@H:40]([NH2:42])[CH3:41])=[N:37][CH:36]=1.C(N(C(C)C)CC)(C)C.C1CN(C(ON2N=NC3C2=CC=CC=3)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl.O>[F:44][C:34]([F:33])([F:43])[C:35]1[NH:39][C:38]([C@@H:40]([NH:42][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:22])[CH3:41])=[N:37][CH:36]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 13685355O-(Benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium HexafluorophosphateHCID 712796202-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acidHCID 71279885(S)-1-(5-(trifluoromethyl)-1H-imidazol-2-yl)ethanamine hydrochloride

Product 1

HCID 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]-amideYield 62.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

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 (40 mg, 90.6 μmol), (S)-1-(5-(trifluoromethyl)-1H-imidazol-2-yl)ethanamine hydrochloride (32.5 mg, 151 μmol), diisopropylethylamine (63.3 μL, 362 μmol) in DMF (2 mL) was added o-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate (43.0 mg, 99.7 μmol). After 15 hours the reaction mixture was diluted with dichloromethane and water. The organic layer was washed with saturated sodium carbonate and brine then dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 12 g Analogix column, 50-70% ethyl acetate in hexanes, gradient over 30 min) to give 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, 62%) as a light yellow solid. LCMS, [M+H]=603.

Workup

  1. washThe organic layer was washed with saturated sodium carbonate and brine
  2. dry with materialthen dried (sodium sulfate)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by chromatography (silica, 12 g Analogix column, 50-70% ethyl acetate in hexanes, gradient over 30 min)

Sources & evidence

ORD record
ord-585f4d46e9f248f4b4f0bceec06a715f
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Linked notes

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