Sodium t-butoxide → 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-5,7-difluoro-3-methyl-2-(1-piperidinyl)quinoline

HRID 1618576Notes

Reaction equation

HRID 1618576 reaction equation
C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:47])=[CH:43][C:44]=2[F:46])[N:39]=[C:38]([N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[C:37]=1[CH3:54].[CH3:55][C:56]1([CH3:71])[C:64]2[C:59](=[CH:60][C:61]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[CH:62][CH:63]=2)[NH:58][CH2:57]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.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]>[CH3:55][C:56]1([CH3:71])[C:64]2[C:59](=[CH:60][C:61]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[CH:62][CH:63]=2)[N:58]([C:36]2[C:45]3[C:40](=[CH:41][C:42]([F:47])=[CH:43][C:44]=3[F:46])[N:39]=[C:38]([N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:37]=2[CH3:54])[CH2:57]1

Participants

8

Reactant 4

HCID 23676156Sodium t-butoxideHCID 596311534-Chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinolineHCID 672848583,3-Dimethyl-6-morpholinoindolineHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Product 1

HCID 509386034-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-5,7-difluoro-3-methyl-2-(1-piperidinyl)quinoline

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

The 2-(dicyclohexylphosphino)-2,4,6-tri-i-propyl-1,1-biphenyl (9.85 mg, 0.021 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinoline (38.3 mg, 0.129 mmol), 4-(3,3-dimethylindolin-6-yl)morpholine (30.0 mg, 0.129 mmol), sodium tert-butoxide (31.0 mg, 0.323 mmol) and Pd2(dba)3 (4.73 mg, 5.17 μmol) were slurried in toluene (1.00 mL) in a sealed tube and heated to 110° C. for 45 minutes. The reaction was cooled to rt and diluted with water (˜20 mL). This mixture was extracted with EtOAc (1×50 mL) and DCM (1×50 mL). The combined organic layers were dried over magnesium sulfate and the crude product was purified by medium pressure chromatography (silica, 0 to 100% EtOAc:hexane) to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-5,7-difluoro-3-methyl-2-(1-piperidinyl)quinoline. 1H NMR (CDCl3) δ ppm 7.31 (1H, br. s.), 7.02 (1H, d, J=8.1 Hz), 6.68 (1H, ddd, J=11.7, 9.1, 2.4 Hz), 6.26 (1H, d, J=7.3 Hz), 5.46 (1H, br. s.), 3.67-3.80 (5H, m), 3.59 (1H, d, J=8.8 Hz), 3.32 (4H, br. s.), 2.94 (4H, d, J=3.7 Hz), 2.24 (3H, s), 1.65-1.86 (6H, m), 1.45 (3H, s), 1.42 (3H, s). Mass Spectrum (ESI) m/e=493.3 (M+1).

Workup

  1. temperatureThe reaction was cooled to rt
  2. extractionThis mixture was extracted with EtOAc (1×50 mL) and DCM (1×50 mL)
  3. dry with materialThe combined organic layers were dried over magnesium sulfate
  4. customthe crude product was purified by medium pressure chromatography (silica, 0 to 100% EtOAc:hexane)

Sources & evidence

ORD record
ord-c5b5118f96e64d61a579fcf64df6bac5
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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