Anisole → N1-(4-(2-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide

HRID 1670211Notes

Reaction equation

COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:26])=[CH:18][C:17]=3[F:36])[CH:12]=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:26])=[CH:18][C:17]=2[F:36])[CH:12]=[CH:11][N:10]=1

Participants

Conditions

Temperature: 85 °C

Procedure

A mixture of N1-(4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (Example 14, 25 mg, 0.048 mmol), anisole (52 mg, 0.48 mmol) in TFA (1 mL) was heated at 85° C. for 6 h. The TFA was removed under vacuum and the residue partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was washed with brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography on SiO2 using EtOAc then 1-2% MeOH in CH2Cl2 as eluents gave the title compound (12 mg, 63%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.51 (s, 1H), 8.02 (s, 1H), 7.66 (dd, 1H, J=12.6, 2.0 Hz), 7.42-7.31 (m, 2H), 7.32-7.27 (m, 1H), 7.23 (t, 2H, J=8.6 Hz), 7.16 (t, 2H, J=9.1 Hz), 6.91 (s, 2H), 3.73 (s, 2H); MS (ESI+) m/z 400.11 (M+H)+.

Workup

customThe TFA was removed under vacuum
customthe residue partitioned between EtOAc and saturated aq. NaHCO3 solution
washThe EtOAc phase was washed with brine
dry with materialdried (MgSO4)
concentrationconcentrated in vacuo

Sources & evidence

ORD record: ord-3e1d8f253bc247fc961e2bbb24cdeaa4
Source dataset: uspto-grants-2011_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07989477B2

Reaction notes

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