Ethyl Acetate → 5-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamide

HRID 595648Notes

Reaction equation

HRID 595648 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[C:29]1C=N[C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)=[O:4].Cl[C:40]1[CH:49]=[CH:48][C:47]2[CH2:46][CH2:45][N:44]3[C:50]4[CH:51]=[CH:52][CH:53]=[C:54]([F:57])[C:55]=4[CH:56]=[C:43]3[C:42]=2[N:41]=1.[CH3:58][CH:59](C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(=O)OCC>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:57][C:54]1[C:55]2[CH:56]=[C:43]3[C:42]4[N:41]=[C:40]([C:13]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]6[O:7][C:6]([C:29]7[CH:59]=[CH:58][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=7)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:8]=5)[CH:49]=[CH:48][C:47]=4[CH2:46][CH2:45][N:44]3[C:50]=2[CH:51]=[CH:52][CH:53]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 90333610N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)benzofuran-3-carboxamideHCID 903336312-Chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine

Product 1

HCID 1185735765-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxamideYield 264.1%

Reagents, catalysts & solvents 2

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

Procedure

A mixture of N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)benzofuran-3-carboxamide (121 mg, 0.22 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and K3CO3 (51 mg, 0.37 mmol) in dioxane/water (2 mL/0.4 mL) was stirred at room temperature for 10 min under N2 protection. Then Pd2(dba)3 (18 mg, 0.02 mmol) and X-Phos (17 mg, 0.04 mmol) were added to the reaction solution. The mixture was stirred at 90° C. for 2 hours under N2 protection. The mixture was then cooled to room temperature, added EA (10 mL) and then filtered through a Celite pad. The combined organic phase was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the desired product (crude: 70 mg, yield: 58%). 1H-NMR (CDCl3, 400 MHz) δ 9.29 (s, 1H), 8.63 (d, J=7.2 Hz, 1H), 7.95 (s, 1H), 7.67˜7.79 (m, 3H), 7.45 (d, J=7.6 Hz, 3H), 7.14˜7.24 (m, 3H), 6.78˜6.80 (m, 1H), 6.14˜6.15 (m, 1H), 4.33 (t, J=6.8 Hz, 1H), 3.29˜3.33 (m, 5H), 3.02 (d, J=4.8 Hz, 3H), 2.74 (s, 3H). MS (M+H)+: 663.

Workup

  1. stirringThe mixture was stirred at 90° C. for 2 hours under N2 protection
  2. temperatureThe mixture was then cooled to room temperature
  3. filtrationfiltered through a Celite pad
  4. washThe combined organic phase was washed with water and brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue was purified by prep-HPLC

Sources & evidence

ORD record
ord-8b105f7a4d474595beed1bdf416afe31
Source dataset
uspto-grants-2016_01
Patent number
US09243002B2

Reaction notes

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