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

HRID 595662Notes

Reaction equation

HRID 595662 reaction equation
[CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[N:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]1=[O:36])=[O:4].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+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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]>[F:55][C:52]1[C:53]2[CH:54]=[C:41]3[C:40]4[N:39]=[C:38]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([N:29]7[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]7=[O:36])=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:10]=5)[CH:47]=[CH:46][C:45]=4[CH2:44][CH2:43][N:42]3[C:48]=2[CH:49]=[CH:50][CH:51]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 90333625N-methyl-2-(4-methyl-2-oxopyridin-1 (2H)-yl)-6-(N-methylmethylsulfonamido)-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 778451105-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-N-methyl-2-(4-methyl-2-oxopyridin-1 (2H)-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamideYield 25.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
80 °C

Procedure

To a mixture of N-methyl-2-(4-methyl-2-oxopyridin-1 (2H)-yl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.19 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (63 mg, 0.23 mmol) and K2CO3 (54 mg, 0.39 mmol) in 1,4-dioxane/H2O (3 mL/0.1 mL) were added X-Phos (10 mg) and Pd2(dba)3 (10 mg) under N2. The reaction mixture was stirred at 80° C. for 5 hours and concentrated in vacuo to remove 1,4-dioxane. The reaction mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the product (30 mg, yield: 24%). 1H-NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 7.83˜7.85 (m, 1H), 7.66˜7.68 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.26˜7.18 (m, 2H), 7.14˜7.18 (m, 2H), 6.77˜6.81 (m, 1H), 6.53 (s, 1H), 6.29 (d, J=8.0 Hz, 1H), 4.34 (t, J=6.4 Hz, 2H), 3.40 (s, 3H), 3.31 (t, J=6.4 Hz, 2H), 2.90 (d, J=4.8 Hz, 3H), 2.61 (s, 3H), 2.32 (s, 3H). MS (M+H)+: 626.

Workup

  1. concentrationconcentrated in vacuo
  2. customto remove 1,4-dioxane
  3. extractionThe reaction mixture was extracted with EtOAc
  4. washwashed 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-520e1d8559d34964bfa4b0d0d5b4c4e5
Source dataset
uspto-grants-2016_01
Patent number
US09243002B2

Reaction notes

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