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

HRID 69253

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][NH:25][CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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]([CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1

Participants

Conditions

Temperature: 95 °C

Procedure

A mixture of 7-fluoro-6-[6-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 251, 50 mg, 0.145 mmol), 1-(2-chlorethyl)pyrrolidine hydrochloride (25 mg, 0.145 mmol) and Cs2CO3 (99 mg, 0.305 mmol) in DMF (1 mL) was stirred at 95° C. for 18 h. 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 as a foam (tR 3.06 min (conditions 3), MH+=442.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.44 (s, 1H); 8.34 (d, 1H); 8.08 (m, 2H); 8.03 (d, 1H); 7.76 (d, 1H); 7.61 (s, 1H); 7.52 (d, 1H); 7.46 (dd, 1H); 4.54 (s, 2H); 4.26 (t, 2H); 2.83 (m, 2H); 2.44 (m, 4H); 1.62 (m, 4H)).

Workup

washwashed with NaHCO3 and brine
dry with materialThe organic layer was dried over Na2SO4
filtrationfiltered
concentrationconcentrated
customThe residue was purified by flash chromatography (CombiFlash® Companion System®

Sources & evidence

ORD record: ord-32e9cffa9aaf45e5a0cf84a84dce0295
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08822468B2

Linked notes

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