Trifluoroacetic acid → HCID 71280416, compound

HRID 246403Notes

Reaction equation

HRID 246403 reaction equation
[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 71279969HCID 71279969, compound

Product 1

HCID 71280416HCID 71280416, compoundYield 81.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a pale yellow solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (97 mg, 158 μmol) in dichloromethane (4 mL) was added TFA (1.48 g, 1 mL, 13.0 mmol, Eq: 82.4), the reaction mixture turned orange and was stirred at 25° C. for 2 h, mixture concentrated and 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 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane (with a couple of drops of MeOH) and purified by chromatography (40 g column, 20-40 μm spherical silica, HP Gold from Teledyne/Isco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, off-white solid was separated by decantation and dried under high vacuum to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62 mg, 128 μmol, 81.1%). MS (M+H)+=486 (100% purity); 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.78-7.95 (m, 2H), 7.39 (d, J=8.7 Hz, 1H), 7.19 (s, 1H), 4.55 (t, J=6.2 Hz, 2H), 2.17-2.30 (m, 2H), 2.12 (s, 7H), 1.99-2.07 (m, 2H), 1.49 (s, 10H).

Workup

  1. concentrationmixture 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 1 h
  4. customevaporated to a yellow solid, which
  5. dissolutionwas dissolved in dichloromethane (with a couple of drops of MeOH)
  6. custompurified by chromatography (40 g column, 20-40 μm spherical silica, HP Gold from Teledyne/Isco)
  7. washeluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane
  8. dissolutionThe pure product dissolved in dichloromethane
  9. additioncyclohexane added
  10. customwas separated by decantation
  11. customdried under high vacuum

Sources & evidence

ORD record
ord-7feff77dbafe4e3490fd03db36597ec3
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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