Trifluoroacetic acid → HCID 178467448, compound

HRID 2405894Notes

Reaction equation

HRID 2405894 reaction equation
[CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](F)[N:14]=3)[C:5]=12)[CH3:2].[CH2:39]([C@H:43]1[CH2:48][NH:47][CH2:46][CH2:45][N:44]1C(OC(C)(C)C)=O)[CH:40]([CH3:42])[CH3:41].CCN(C(C)C)C(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CS(C)=O.O.C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[NH:10][N:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:47]4[CH2:46][CH2:45][NH:44][CH:43]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:48]4)[N:14]=3)[C:5]=12)[CH3:2]

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 12052TriethylsilaneHCID 81531DiisopropylethylamineHCID 17750437tert-Butyl (2S)-2-(2-methylpropyl)piperazine-1-carboxylateHCID 68253483HCID 68253483, compound

Product 1

HCID 178467448HCID 178467448, compoundYield 1.8%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
150 °C

Procedure

4-ethoxy-3-(6-fluoro-2-pyridyl)-1-trityl-pyrazolo[3,4-d]pyrimidine (139 mg, 0.27 mmol), (S)-tert-butyl 2-isobutylpiperazine-1-carboxylate (201.5 mg, 0.83 mmol) and DIPEA (214.9 mg, 289.6 μL, 1.66 mmol) were dissolved in DMSO (3.5 mL) and the reaction mixture was heated at 150° C. for 5 hours under microwave conditions. After this time, the reaction mixture was allowed to cool and DCM and water were added. The organic layer was separated dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 40 g column, eluting with MeOH/DCM). The fractions were isolated and concentrated in vacuo. The residue was taken up in DCM (10 mL) and triethylsilane (128.8 mg, 176.9 μL, 1.11 mmol) and TFA (631.9 mg, 427.0 μL, 5.54 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. After this time the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 5 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions were isolated and freeze-dried to give the di-TFA salt of the title compound as a solid (1.9 mg, 1% Yield). H1 NMR (400 MHz, DMSO) δ 14.13 (brs, 1H), 8.98-8.60 (m, 2H), 8.58 (s, 1H), 7.83-7.67 (m, 1H), 7.31 (brs, 1H), 4.66-4.48 (m, 3H), 3.80-3.00 (m, 5H), 3.00-2.88 (m, 1H), 1.86-1.72 (m, 1H), 1.54-1.31 (m, 5H), 0.91 (d, J=6.5 Hz, 3H) and 0.85 (d, J=6.5 Hz, 3H) ppm; MS (ES+) 382.0.

Workup

  1. temperatureto cool
  2. customThe organic layer was separated
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude mixture was purified by column chromatography (ISCO Companion™, 40 g column, eluting with MeOH/DCM)
  7. customThe fractions were isolated
  8. concentrationconcentrated in vacuo
  9. concentrationAfter this time the reaction mixture was concentrated in vacuo
  10. customThe residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 5 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions
  11. customwere isolated
  12. customfreeze-dried

Sources & evidence

ORD record
ord-f39538305b6c4ea5a4310efc7b63c4da
Source dataset
uspto-grants-2014_08
Patent number
US08809335B2

Reaction notes

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