Toluene → N-(2,5-Di-4-morpholinylphenyl)-7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinamine

HRID 1431271Notes

Reaction equation

HRID 1431271 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH3:27])[CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:28]1([C:5]2[CH:4]=[CH:3][C:2]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:7][C:6]=2[NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH3:27])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1

Participants

7

Reactant 5

HCID 1140TolueneHCID 8083MorpholineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 59631174N-(5-Bromo-2-morpholinophenyl)-7-fluoro-2-(2-fluorophenyl)-3-methylquinolin-4-amine

Product 1

HCID 59631208N-(2,5-Di-4-morpholinylphenyl)-7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinamine

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Procedure

A mixture of N-(5-bromo-2-morpholinophenyl)-7-fluoro-2-(2-fluorophenyl)-3-methylquinolin-4-amine (50 mg, 98 μmol), morpholine (0.017 mL, 196 μmol), tris(dibenzylideneacetone)dipalladium(0) (6.3 mg, 6.9 μmol), X-Phos (7.0 mg, 15 μmol) and sodium tert-butoxide (19 mg, 196 μmol) in toluene (4.00 mL, 37552 μmol) was degassed by evacuation-back fill 3× then heated to reflux in an oil bath for 90 min, after which time LC-MS indicated only desired product predominated. The reaction was equilibrated to rt, concd under reduced pressure and the concentrate partitioned between 25 mL each DCM and water. The organic separation was stirred over anhydrous magnesium sulfate, filtered and the filtrate concd under reduced pressure to afford a yellow-brown solid. The product was isolated by reversed phase HPLC on Phenomenex™ C18 column, eluting with MeCN/water+0.1% TFA. 1H NMR (400 MHz, chloroform-d) δ ppm 7.83 (1H, dd, J=9.2, 6.1 Hz), 7.70 (1H, dd, J=10.0, 2.5 Hz), 7.52 (1H, td, J=7.4, 2.0 Hz), 7.33-7.45 (1H, m, J=7.9, 7.9, 5.4, 2.0 Hz), 7.15-7.30 (3H, m), 7.06-7.15 (1H, m), 7.03 (1H, d, J=8.6 Hz), 6.36 (1H, dd, J=8.6, 2.7 Hz), 5.96 (1H, d, J=2.0 Hz), 3.83 (4H, t, J=4.5 Hz), 3.58-3.75 (4H, m), 2.97 (4H, d, J=2.7 Hz), 2.75-2.92 (4H, m), 2.11 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=517.2 (M+1).

Workup

  1. customwas degassed by evacuation-back fill 3×
  2. temperaturethen heated
  3. temperatureto reflux in an oil bath for 90 min
  4. customwas equilibrated to rt
  5. customconcd under reduced pressure and the concentrate partitioned between 25 mL each DCM and water
  6. customThe organic separation
  7. filtrationfiltered
  8. customthe filtrate concd under reduced pressure to afford a yellow-brown solid
  9. customThe product was isolated by reversed phase HPLC on Phenomenex™ C18 column
  10. washeluting with MeCN/water+0.1% TFA

Sources & evidence

ORD record
ord-2f60b27fa9df417a95b9c239a39fd311
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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