Diisopropylethylamine → N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

HRID 415892Notes

Reaction equation

HRID 415892 reaction equation
[OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10](O)=[O:11])[C:6](=[O:13])[N:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.CN([C:34]([O:38]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:55][C:56]1[CH:57]=[C:58]([NH2:75])[CH:59]=[CH:60][C:61]=1[O:62][C:63]1[C:72]2[C:67](=[CH:68][C:69]([O:73][CH3:74])=[CH:70][CH:71]=2)[N:66]=[CH:65][CH:64]=1>CN(C=O)C.ClCCl>[CH3:34][O:38][C:70]1[CH:71]=[C:72]2[C:67](=[CH:68][C:69]=1[O:73][CH3:74])[N:66]=[CH:65][CH:64]=[C:63]2[O:62][C:61]1[CH:60]=[CH:59][C:58]([NH:75][C:10]([C:7]2[C:6](=[O:13])[N:5]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]([CH2:3][C:2]([OH:1])([CH3:21])[CH3:20])[C:8]=2[CH3:9])=[O:11])=[CH:57][C:56]=1[F:55]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 533934301-(2-Hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazole-4-carboxylic AcidHCID 595983543-Fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine

Product 1

HCID 11962892N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamideYield 74%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
37 °C

Procedure

To a stirring solution of 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (104 mg, 358 μmol) and diisopropylethylamine (62 μl, 358 μmol) in DMF (1 mL) was added HATU (136 mg, 358 μmol) and stirred at 37° C. under nitrogen for 15 min. To this was added 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (98 mg, 344 mmol) and stirred overnight at 37° C. The reaction mixture was diluted with dichloromethane (10 mL) and washed with 1M NaOH (20 mL), and extracted with dichloromethane (3×5 mL). Combined organics layer was washed with brine and then dried with MgSO4. Residual DMF was removed with repeated azeotroping with toluene (4×5 mL) under reduced pressure. The residue was purified on 12 g silica (10>30% of 6% 2 M NH3 in MeOH/DCM). Final material was lyophilized from 50% ACN/water to give the title compound (155 mg, 74% yield) as a white fluffy solid. MS (ESI pos. ion) m/z: 587 (MH+). Calc'd exact mass for C32H31FN4O6 587. 1H NMR (400 MHz, CHLOROFORM-d) 10.88 (1 H, s), 8.47 (1 H, d, J=5.3 Hz), 7.92 (1 H, dd, J=12.5, 2.0 Hz), 7.59 (1 H, s), 7.54 (2 H, t, J=7.7 Hz), 7.40-7.49 (2 H, m), 7.30 (3 H, d, J=7.8 Hz), 7.17 (1 H, t, J=8.7 Hz), 6.45 (1 H, d, J=5.3 Hz), 4.06 (3 H, s), 4.05 (3 H, s), 3.88 (2 H, s), 2.89 (3 H, s), 2.01 (1 H, s), 1.15(6 H, s)

Workup

  1. stirringstirred overnight at 37° C
  2. washwashed with 1M NaOH (20 mL)
  3. extractionextracted with dichloromethane (3×5 mL)
  4. washCombined organics layer was washed with brine
  5. dry with materialdried with MgSO4
  6. customResidual DMF was removed
  7. customwith repeated azeotroping with toluene (4×5 mL) under reduced pressure
  8. customThe residue was purified on 12 g silica (10>30% of 6% 2 M NH3 in MeOH/DCM)

Sources & evidence

ORD record
ord-07ecf0014dca49a0b04cb0bbd9f7c8e3
Source dataset
uspto-grants-2012_01
Patent number
US08088794B2

Reaction notes

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