2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(4-methyl-2-pyridinyl)quinoline

HRID 1618679Notes

Reaction equation

HRID 1618679 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=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.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]>[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](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:20])[CH2:23]1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596310864-Chloro-7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinolineHCID 672844994-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-morpholine

Product 1

HCID 672850644-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(4-methyl-2-pyridinyl)quinoline

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

Prepared according to procedure Y by heating 4-chloro-7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (70 mg, 0.244 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (57.0 mg, 0.244 mmol), XPhos (23.3 mg, 0.049 mmol), Pd2dba3 (22.4 mg, 0.024 mmol) and sodium tert butoxide (46.9 mg, 0.488 mmol) in toluene (2.0 mL) at 110° C. in a microwave reactor for 2 h. After this time the reaction was partitioned between EtOAc (70 mL) and water (30 mL). The separated aqueous layer was extracted with EtOAc (30 mL) and the combined organic layers were dried over MgSO4, filtered and evaporated in vacuo. Reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(4-methyl-2-pyridinyl)quinoline. 1H NMR (500 MHz, chloroform-d) δ ppm 8.59 (1H, d, J=4.9 Hz), 7.84 (1H, dd, J=10.0, 2.7 Hz), 7.79 (1H, dd, J=9.3, 6.1 Hz), 7.66-7.70 (1H, m), 7.59 (1H, d, J=2.2 Hz), 7.27-7.32 (1H, m), 7.22 (1H, dd, J=5.0, 1.8 Hz), 5.81 (1H, d, J=2.4 Hz), 3.79-3.83 (2H, m), 3.72-3.78 (4H, m), 2.92-3.05 (4H, m), 2.47-2.52 (3H, m), 2.36 (3H, s), 1.57 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=484.2 (M+1).

Workup

  1. customPrepared
  2. customAfter this time the reaction was partitioned between EtOAc (70 mL) and water (30 mL)
  3. extractionThe separated aqueous layer was extracted with EtOAc (30 mL)
  4. dry with materialthe combined organic layers were dried over MgSO4
  5. filtrationfiltered
  6. customevaporated in vacuo

Sources & evidence

ORD record
ord-dc81dcb176fa4c81b17752b2174344a3
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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