1,8-Diazabicyclo(5.4.0)undec-7-ene → 1-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea

HRID 1098608Notes

Reaction equation

HRID 1098608 reaction equation
[CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1.[F:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH:31][C:32](=O)[O:33]C(C)=C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:32]([NH:31][C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)[CH:20]=4)=[CH:17][C:12]=3[F:11])=[O:33])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 27353113-cyclopropyl-1-methyl-1H-pyrazol-5-amineHCID 66729122prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate

Product 1

HCID 667289381-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureaYield 13.4%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (60 mg, 0.434 mmol) in dioxane (1 mL) was added prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate from Example 21 (0.16 g, 0.434 mmol), and DBU (6.61 mg, 0.043 mmol) and the mixture was stirred overnight at 70° C. The reaction was checked by LC-MS, solvent was removed and the residue was purified by silica gel column chromatography (EtOAc/hexane→CH2Cl2/MeOH). Pure fractions were combined and concentrated. The residue was dissolved in CH3CN:H2O (1:1, 2 mL) and lyophilized to obtain 1-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (26 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.39 (d, J=6.0 Hz, 1H), 8.28 (s, 1H), 8.18 (t, J=9.6 Hz, 1H), 7.99 (s, 1H), 7.26 (m, 2H), 7.02 (m, 1H), 6.70 (dd, J=2.4, and 6.0 Hz, 1H), 3.87 (s, 3H), 3.59 (s, 3H), 1.76 (m, 1H), 0.80 (m, 2H), 0.59 (m, 2H); MS (ESI) m/z; 448.1 (M+H+).

Workup

  1. customwas removed
  2. customthe residue was purified by silica gel column chromatography (EtOAc/hexane→CH2Cl2/MeOH)
  3. concentrationconcentrated
  4. dissolutionThe residue was dissolved in CH3CN:H2O (1:1, 2 mL)

Sources & evidence

ORD record
ord-d191debc2b9f4132a3a25feb91cc17c6
Source dataset
uspto-grants-2012_03
Patent number
US08143293B2

Reaction notes

Loading…