Cesium carbonate → 5-(6-(4-fluoro-1H-indol-2-yl)-5-(3-hydroxypropyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

HRID 595741

Reaction equation

HRID 595741 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH2:34][CH2:35][CH2:36][OH:37].[F:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[C:42](B1OC(C)(C)C(C)(C)O1)[NH:43]2.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2].O>[F:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[C:42]([C:2]1[N:7]=[C:6]([C:8]3[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])=[CH:10][C:11]4[O:15][C:14]([C:16]5[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=5)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=4[CH:27]=3)[CH:5]=[CH:4][C:3]=1[CH2:34][CH2:35][CH2:36][OH:37])[NH:43]2

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 532172124-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)-1H-indoleHCID 903325055-(6-chloro-5-(3-hydroxypropyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

Product 1

HCID 903336015-(6-(4-fluoro-1H-indol-2-yl)-5-(3-hydroxypropyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

Reagents, catalysts & solvents 2

HCID 53384307Dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II)CatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

To a mixture of 5-(6-chloro-5-(3-hydroxypropyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (180 mg, 0.330 mmol), 4-fluoroindole-2-boronic acid pinacol ester (129 mg, 0.494 mmol), cesium carbonate (215 mg, 0.659 mmol) and dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium (II) (21.49 mg, 0.033 mmol) was added 1,4-dioxane (3 mL) and H2O (0.3 mL). A steady stream of N2 was bubbled through the reaction mixture for 5 minutes then the mixture was heated to 90° C. for 3 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc/CH2Cl2 as eluent. The residue was triturated with CH2Cl2 to provide the title compound as a white solid. 1H NMR δ (ppm) (CHCl3-d): 10.30 (1H, br s), 8.07 (1H, s), 8.00 (2H, dd, J=8.56, 5.31 Hz), 7.78 (1H, d, J=7.88 Hz), 7.69 (1H, s), 7.50 (1H, d, J=7.85 Hz), 7.27˜7.23 (3H, m), 7.17˜7.13 (2H, m), 6.81˜6.78 (1H, m), 5.93˜5.87 (1H, m), 3.89 (2H, d, J=5.37 Hz), 3.24 (2H, t, J=7.86 Hz), 3.16 (3H, s), 3.02 (3H, d, J=4.90 Hz), 2.92 (3H, s), 2.13 (2H, t, J=7.43 Hz). MS (M+H)+: 645.

Workup

  1. customA steady stream of N2 was bubbled through the reaction mixture for 5 minutes
  2. temperatureThe mixture was cooled to ambient temperature
  3. additiondiluted with EtOAc
  4. washwashed successively with H2O (1×) and brine (1×)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by silica gel column chromatography
  9. customThe residue was triturated with CH2Cl2

Sources & evidence

ORD record
ord-0ceb285e9eac4b489da8f8f646d55bd0
Source dataset
uspto-grants-2016_01
Patent number
US09243002B2

Linked notes

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