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

HRID 1618648Notes

Reaction equation

HRID 1618648 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.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:30]=1[CH3:47]>CCOC(C)=O>[F:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([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:30]([CH3:47])[C:31]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[F:46])=[N:32]2)=[CH:37][CH:36]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 596313954-Chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinolineHCID 672846616-Morpholino-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]

Product 1

HCID 509399891-(7-Fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran]

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.19 g, 0.69 mmol) was dissolved in DMF (2.00 mL, 26 mmol) and sodium hydride (0.018 g, 0.76 mmol) was added and the reaction was treated with 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (0.100 g, 0.35 mmol) and heated to 140° C. for 6 h. The reaction was then diluted with EtOAc and washed with 2% sodium bicarbonate then brine. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The reaction was then purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane and then purified by preparative reverse phase HPLC to afford 1-(7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=528.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.99 (1H, m), 7.83 (1H, dd, J=10.2, 2.3 Hz), 7.50-7.62 (3H, m), 7.35-7.42 (2H, m), 7.10 (1H, d, J=8.2 Hz), 6.29 (1H, dd, J=8.2, 2.3 Hz), 5.56 (1H, d, J=2.3 Hz), 4.07 (1H, d, J=9.8 Hz), 3.80-3.91 (3H, m), 3.56-3.63 (4H, m), 3.41-3.54 (2H, m), 2.82-2.89 (4H, m), 2.05 (3H, d, J=1.2 Hz), 1.90-2.02 (2H, m), 1.81-1.88 (1H, m), 1.62-1.72 (1H, m)

Workup

  1. washwashed with 2% sodium bicarbonate
  2. customThe layers were separated
  3. dry with materialthe organic layer was dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe reaction was then purified by flash column chromatography
  7. washeluting with 40% to 60% EtOAc in hexane
  8. custompurified by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-88b4fd8177094a169d5eaa9cb2468880
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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