Trifluoroacetic acid → 2-(1-(2-(azetidin-3-yl)ethyl)-6-fluoro-1H-indazol-3-yl)-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246435Notes

Reaction equation

HRID 246435 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][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][CH:29]4[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[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>[NH:31]1[CH2:30][CH:29]([CH2:28][CH2:27][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][NH:10][C:11]4=[N:12][CH:13]=3)=[N:18]2)[CH2:32]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 71280628tert-butyl 3-(2-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)ethyl)azetidine-1-carboxylate

Product 1

HCID 712806832-(1-(2-(azetidin-3-yl)ethyl)-6-fluoro-1H-indazol-3-yl)-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 81.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a pale yellow solution of tert-butyl 3-(2-(3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)ethyl)azetidine-1-carboxylate (43 mg, 64.6 μmol) in dichloromethane (4.00 mL) was added TFA (740 mg, 500 μL, 6.49 mmol00), the reaction mixture turned orange and was stirred at 25° C. for 18 h. The reaction mixture was 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 (added few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 30 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane with few drops of MeOH and cyclohexane added to allow solid formation, off-white solid separated by decantation and dried under high vacuum to give 2-(1-(2-(azetidin-3-yl)ethyl)-6-fluoro-1H-indazol-3-yl)-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 52.8 μmol, 81.8%). MS (M+H)+=436; 1H NMR (DMSO-d6) δ: 9.08 (s, 1H), 8.48 (dd, J=8.7, 5.3 Hz, 1H), 8.39 (s, 1H), 7.90 (s, 1H), 7.77 (dd, J=9.8, 1.9 Hz, 1H), 7.16 (td, J=9.1, 1.9 Hz, 1H), 4.49 (t, J=6.6 Hz, 2H), 3.68-3.85 (m, 2H), 3.44-3.56 (m, 2H), 2.75 (dt, J=15.2, 7.7 Hz, 1H), 2.20 (q, J=6.7 Hz, 2H), 1.51 (s, 9H).

Workup

  1. concentrationThe reaction mixture was 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 (added few drops of MeOH)
  6. custompurified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco)
  7. washeluting with 0 to 10% over 30 min (MeOH containing 10% ammonium hydroxide)/dichloromethane
  8. dissolutionThe pure product dissolved in dichloromethane with few drops of MeOH and cyclohexane
  9. additionadded
  10. customseparated by decantation
  11. customdried under high vacuum

Sources & evidence

ORD record
ord-3739c3ab058a43b189c2d80084e6e30d
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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