2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-fluoro-3,8-dimethyl-2-(2-pyridin-yl)quinoline

HRID 1618570Notes

Reaction equation

HRID 1618570 reaction equation
Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:20].[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[NH:24][CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[N:24]([C:2]2[C:11]3[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:3]=2[CH3:20])[CH2:23]1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596312654-Chloro-5-fluoro-3,8-dimethyl-2-(pyridin-2-yl)quinolineHCID 672844994-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-morpholine

Product 1

HCID 509386054-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-fluoro-3,8-dimethyl-2-(2-pyridin-yl)quinoline

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 4-chloro-5-fluoro-3,8-dimethyl-2-(pyridin-2-yl)quinoline (30 mg, 0.11 mmol) (described herein), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-6-yl)morpholine (29.3 mg, 0.13 mmol) (described herein), Pd2dba3 (9.58 mg, 10.5 μmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (9.98 mg, 0.021 mmol), sodium tert-butoxide (30.2 mg, 0.314 mmol), and toluene (1.0 mL) was stirred at 100° C. for 18 h, then cooled to rt and concentrated. The resulting residue was taken up in EtOAc, washed with saturated aqueous sodium bicarbonate solution, 1M NaOH, and brine, and the organic layer dried (MgSO4) and concentrated. Chromatography afforded 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-fluoro-3,8-dimethyl-2-(2-pyridin-yl)quinoline as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.69-8.76 (1H, m), 8.02-8.07 (1H, m), 7.92 (1H, td, J=7.7, 1.9 Hz), 7.50-7.56 (1H, m), 7.43-7.50 (1H, m), 7.34-7.43 (1H, m), 7.05 (1H, dd, J=12.2, 7.9 Hz), 5.70-5.75 (1H, m), 3.86 (1H, dt, J=8.9, 0.7 Hz), 3.68-3.79 (5H, m), 2.93-3.05 (4H, m), 2.79 (3H, s), 2.50 (3H, s), 1.56 (3H, s), 1.50 (3H, s). Mass Spectrum (ESI) m/e=484 (M+1).

Workup

  1. temperaturecooled to rt
  2. concentrationconcentrated
  3. washwashed with saturated aqueous sodium bicarbonate solution, 1M NaOH, and brine
  4. dry with materialthe organic layer dried (MgSO4)
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-155fbfdb18404ab1bb2aee20331dc4e7
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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