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

HRID 595688Notes

Reaction equation

HRID 595688 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:25][C:11]3=[N:12][C:13]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[C:14](B(O)O)[CH:15]=[C:10]3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.Cl[C:31]1[CH:40]=[CH:39][C:38]2[CH2:37][CH2:36][N:35]3[C:41]4[CH:42]=[CH:43][CH:44]=[C:45]([F:48])[C:46]=4[CH:47]=[C:34]3[C:33]=2[N:32]=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:48][C:45]1[C:46]2[CH:47]=[C:34]3[C:33]4[N:32]=[C:31]([C:14]5[CH:15]=[C:10]6[C:9]([C:26]([NH:27][CH3:28])=[O:29])=[C:8]([C:5]7[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=7)[O:25][C:11]6=[N:12][C:13]=5[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[CH:40]=[CH:39][C:38]=4[CH2:37][CH2:36][N:35]3[C:41]=2[CH:42]=[CH:43][CH:44]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 90332448(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridin-5-yl)boronic acidHCID 903336312-Chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine

Product 1

HCID 778459265-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridine-3-carboxamideYield 62.1%

Reagents, catalysts & solvents 3

HCID 962WaterCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a degassed solution of (2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridin-5-yl)boronic acid (100 mg, 0.24 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (60 mg, 0.21 mmol) and K2CO3 (98 mg, 0.72 mmol) in 1,4-dioxane (3 mL) and H2O (5 drops) was added Pd2(dba)3 (10 mg) and X-Phos (10 mg) under nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 2 h, concentrated in vacuo to remove 1,4-dioxane. The residue was diluted with H2O and extracted with DCM. The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified to give the desired product (80 mg, yield: 55%) through the prep-HPLC. 1H-NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 8.00˜8.04 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.21 (t, J=8.8 Hz, 2H), 7.14˜7.16 (m, 2H), 6.75˜6.80 (m, 1H), 5.97 (br s, 1H), 4.33 (t, J=6.4 Hz, 2H), 3.25˜3.32 (m, 5H), 3.18 (s, 3H), 3.00 (d, J=4.8 Hz, 3H). MS (M+H)+: 614.

Workup

  1. concentrationconcentrated in vacuo
  2. customto remove 1,4-dioxane
  3. additionThe residue was diluted with H2O
  4. extractionextracted with DCM
  5. washThe combined organic layers were washed with brine (20 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. custompurified

Sources & evidence

ORD record
ord-91a6ef2910944d39b9fbbfa89fd8ace6
Source dataset
uspto-grants-2016_01
Patent number
US09243002B2

Reaction notes

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