2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 1-(7-Fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran]

HRID 1618526Notes

Reaction equation

HRID 1618526 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=2)[C:23]=1[CH3:40].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].O.CCOC(C)=O>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:23]([CH3:40])[C:24]([C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[N:25]2)=[CH:30][CH:29]=1

Participants

9

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 672846616-Morpholino-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]HCID 672852274-Chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline

Product 1

HCID 509390771-(7-Fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran]

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred solution of 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (86 mg, 0.31 mmol), 4-chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline (90 mg, 0.31 mmol) in toluene (1.7 mL) was added Pd2dba3 (43 mg, 0.047 mmol), XPhos (45 mg, 0.09 mmol) and sodium tert-butoxide (90 mg, 0.94 mmol) and the reaction was heated in the microwave for 1 h at 100° C. After this time the reaction was cooled to rt and treated with EtOAc (100 mL) and water (40 mL). The separated organic layer was washed with NaCl (saturated aqueous solution, 40 mL), dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1-(7-fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.59-8.67 (1H, m), 7.84-7.94 (1H, m), 7.76-7.83 (1H, m), 7.59-7.69 (1H, m), 7.27-7.34 (2H, m), 7.11-7.18 (1H, m), 6.28-6.47 (1H, m), 5.48-5.70 (1H, m), 3.97-4.09 (2H, m), 3.85-3.94 (1H, m), 3.68-3.80 (4H, m), 3.48-3.63 (2H, m), 2.89-3.05 (4H, m), 2.36-2.44 (3H, m), 2.09-2.25 (2H, m), 2.05 (4H, dd, J=4.5, 2.3 Hz), 1.90 (1H, dt, J=13.7, 1.2 Hz), 1.72-1.81 (1H, m). Mass Spectrum (ESI) m/e=525 (M+1).

Workup

  1. temperatureAfter this time the reaction was cooled to rt
  2. washThe separated organic layer was washed with NaCl (saturated aqueous solution, 40 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customPurification by reverse phase HPLC (10 to 60% acetonitrile in water)

Sources & evidence

ORD record
ord-fd0b43b6c0854ecd9f89fbb2a3702c9e
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

Loading…