Cesium carbonate → 7-Fluoro-6-(6-{1-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline

HRID 69190Notes

Reaction equation

HRID 69190 reaction equation
[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 5565652,2,2-Trifluoroethyl Methanesulfonate3×HCID 579174297-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline

Product 1

HCID 579173367-Fluoro-6-(6-{1-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 7-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 50 mg, 0.117 mmol), 2,2,2-trifluoroethyl methanesulfonate (55 μL, 0.468 mmol) and Cs2CO3 (76 mg, 0.234 mmol) in THF (1 mL) was stirred at 70° C. for 2 h. 2,2,2-trifluoroethyl methanesulfonate (69 μL, 0.585 mmol) was then added and the RM was stirred at reflux for 24 h. 2,2,2-trifluoroethyl methanesulfonate (69 μL, 0.585 mmol) was added again and the RM was stirred at reflux for 18 h more. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound (tR 3.74 min (conditions 3), 1H-NMR in DMSO-d6: 8.85 (m, 1H); 8.54 (s, 1H); 8.34 (d, 1H); 8.07 (m, 3H); 7.77 (d, 1H); 7.61 (s, 1H); 7.54 (d, 1H); 7.47 (dd, 1H); 4.55 (s, 2H); 4.39 (m, 1H); 3.67 (m, 2H); 2.94 (m, 4H); 2.16 (m, 2H); 2.00 (m, 2H)).

Workup

  1. stirringthe RM was stirred
  2. temperatureat reflux for 24 h
  3. stirringthe RM was stirred
  4. temperatureat reflux for 18 h more
  5. washwashed with NaHCO3 and brine
  6. dry with materialThe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by flash chromatography (CombiFlash® Companion System®

Sources & evidence

ORD record
ord-d058d44c5d884e4799cbbc5e0aad51ca
Source dataset
uspto-grants-2014_09
Patent number
US08822468B2

Reaction notes

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