Potassium Carbonate → 2-(2,4-difluorophenyl)-5-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

HRID 595655Notes

Reaction equation

HRID 595655 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][C:12]=2[C:13]=1[C:14]([NH:16][CH3:17])=[O:15].Cl[C:38]1[CH:47]=[CH:46][C:45]2[CH2:44][CH2:43][N:42]3[C:48]4[CH:49]=[CH:50][CH:51]=[C:52]([F:55])[C:53]=4[CH:54]=[C:41]3[C:40]=2[N:39]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19]([C:38]3[CH:47]=[CH:46][C:45]4[CH2:44][CH2:43][N:42]5[C:48]6[CH:49]=[CH:50][CH:51]=[C:52]([F:55])[C:53]=6[CH:54]=[C:41]5[C:40]=4[N:39]=3)=[CH:18][C:12]=2[C:13]=1[C:14]([NH:16][CH3:17])=[O:15]

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 712956182-(2,4-difluorophenyl)-N-methyl-6-(N-methylmethyl sulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamideHCID 903336312-Chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine

Product 1

HCID 778455712-(2,4-difluorophenyl)-5-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamideYield 42%

Reagents, catalysts & solvents 4

HCID 962WaterCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2-(2,4-difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (500 mg, 0.96 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (240 mg, 0.87 mmol) and K2CO3. (241 mg, 1.75 mmol) in 1,4-dioxane (5 mL) and H2O (5 drop) were added X-Phos (10 mg) and Pd2(dba)3 (10 mg) under N2. The reaction mixture was stirred at 100° C. for 10 hours and concentrated in vacuo to remove 1,4-dioxane. The reaction mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the product (230 mg, yield: 42%). 1H-NMR (CDCl3, 400 MHz) δ 8.08 (s, 1H), 7.7˜57.81 (m, 1H), 7.66˜7.69 (m, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.15˜7.18 (m, 2H), 6.98˜7.09 (m, 2H), 6.79 (t, J=8.4 Hz, 1H), 5.81 (br s, 1H), 4.35 (t, J=6.4 Hz, 2H), 3.39 (s, 3H), 3.32 (t, J=6.4 Hz, 2H), 2.96 (d, J=4.8 Hz, 3H), 2.68 (s, 3H). MS (M+H)+: 631.

Workup

  1. concentrationconcentrated in vacuo
  2. customto remove 1,4-dioxane
  3. extractionThe reaction mixture was extracted with EtOAc
  4. washThe organic phase was washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by prep-HPLC

Sources & evidence

ORD record
ord-90efcfbd4ac643e0b66c4957b0bea45d
Source dataset
uspto-grants-2016_01
Patent number
US09243002B2

Reaction notes

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