Trifluoroacetic acid → 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246384Notes

Reaction equation

HRID 246384 reaction equation
[F:1][CH:2]([F:39])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:24])=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]2=[N:18][CH:19]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:39][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][C:26]([CH3:29])([CH3:30])[CH2:27][OH:28])=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 712802362-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Product 1

HCID 712799672-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 75.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a pale yellow solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (34.4 mg, 61.4 μmol) in dichloromethane (1.44 mL) was added TFA (426 mg, 288 μL, 3.74 mmol, Eq: 60.9), the reaction mixture turned orange and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give a mixture of 2 compounds, no pure compound obtained. Mixture combined again and purified by preparative TLC (Silica GF 1000 μm, 20×40 cm (Gypsum Binder, Fluorescent Indicator)) to give the desired 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (20 mg, 46.5 μmol, 75.7%) as white needles. MS (M+H)+=431; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.80-7.90 (m, 2H), 7.35-7.42 (m, 1H), 7.18 (t, J=74.4 Hz, 1H), 4.95 (t, J=5.7 Hz, 1H), 4.19 (s, 3H), 3.62 (d, J=5.7 Hz, 2H), 1.42 (s, 6H).

Workup

  1. concentrationthen concentrated
  2. dissolutionThe residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1)
  3. stirringstirred at 25° C. for 3 h
  4. customevaporated to a light yellow solid
  5. dissolutiondissolved in dichloromethane (containing a few drops of MeOH)
  6. custompurified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco)
  7. washeluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane
  8. customto give
  9. additiona mixture of 2 compounds
  10. customno pure compound obtained
  11. custompurified by preparative TLC (Silica GF 1000 μm, 20×40 cm (Gypsum Binder, Fluorescent Indicator))

Sources & evidence

ORD record
ord-ee1abcd6d2ff443696552cc9a17f5609
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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