2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → 1-(7-Fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2-dihydrospiro[indole-3,3'-thietane]1',1'-dioxide

HRID 1618789Notes

Reaction equation

HRID 1618789 reaction equation
CC(C)([O-])C.[Na+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.Cl[C:41]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[N:44]=[C:43]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[C:42]=1[CH3:58].[N:59]1([C:65]2[CH:70]=[C:69]3[NH:71][CH2:72][C:73]4([CH2:76][S:75](=[O:78])(=[O:77])[CH2:74]4)[C:68]3=[CH:67][CH:66]=2)[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C1(C)C=CC=CC=1>[F:51][C:47]1[CH:46]=[C:45]2[C:50]([C:41]([N:71]3[C:69]4[C:68](=[CH:67][CH:66]=[C:65]([N:59]5[CH2:60][CH2:61][O:62][CH2:63][CH2:64]5)[CH:70]=4)[C:73]4([CH2:74][S:75](=[O:77])(=[O:78])[CH2:76]4)[CH2:72]3)=[C:42]([CH3:58])[C:43]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=3)=[N:44]2)=[CH:49][CH:48]=1

Participants

7

Reactant 4

HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 23676156Sodium t-butoxideHCID 596310754-Chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinolineHCID 672849516-(4-Morpholinyl)-1,2-dihydrospiro[indole-3,3'-thietane]1',1'-dioxide

Product 1

HCID 509392121-(7-Fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2-dihydrospiro[indole-3,3'-thietane]1',1'-dioxide

Reagents, catalysts & solvents 2

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a microwave vial was added sodium tert-butoxide (0.017 g, 0.177 mmol), ruphos (4.12 mg, 8.83 μmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)-quinoline (0.025 g, 0.093 mmol), 6-(4-morpholinyl)-1,2-dihydrospiro[indole-3,3′-thietane]1′,1′-dioxide (0.026 g, 0.088 mmol), and XPhos pre-catalyst (6.5 mg, 8.8 mmol) in toluene (0.6 mL). The suspension was deoxygenated with argon for 5 min then stirred at 100° C. for 1 h under microwave irradiation. Purification by column chromatography (eluting with a gradient of 0-10% MeOH in DCM) gave a yellow solid that was repurified by reverse phase HPLC (10-60% acetonitrile in water) to give 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2-dihydrospiro[indole-3,3′-thietane]1′,1′-dioxide as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.71 (1H, d, J=4.89 Hz), 7.99-8.05 (1H, m), 7.83-7.94 (3H, m), 7.50-7.56 (2H, m), 7.49 (1H, d, J=8.31 Hz, 6.40 (1H, dd, J=8.44, 2.08 Hz), 5.58 (1H, d, J=1.96 Hz), 4.72 (1H, dd, J=13.57, 2.32 Hz), 4.55-4.63 (3H, m), 4.35 (1H, d, J=10.03 Hz), 4.25 (1H, d, J=10.03 Hz), 3.58 (4H, t, J=4.89 Hz), 2.82-2.93 (4H, m), 2.24 (3H, s). Mass Spectrum (ESI) m/e=531.2 (M+1).

Workup

  1. customThe suspension was deoxygenated with argon for 5 min
  2. customPurification by column chromatography (
  3. washeluting with a gradient of 0-10% MeOH in DCM)
  4. customgave a yellow solid
  5. customthat was repurified by reverse phase HPLC (10-60% acetonitrile in water)

Sources & evidence

ORD record
ord-f1349790987b49ce9acca1f67776d553
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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