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

HRID 595672Notes

Reaction equation

HRID 595672 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]1[S:33][C:32]([CH3:34])=[N:31][CH:30]=1)=[O:4].Cl[C:36]1[CH:45]=[CH:44][C:43]2[CH2:42][CH2:41][N:40]3[C:46]4[CH:47]=[CH:48][CH:49]=[C:50]([F:53])[C:51]=4[CH:52]=[C:39]3[C:38]=2[N:37]=1.C([O-])([O-])=O.[Na+].[Na+].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:53][C:50]1[C:51]2[CH:52]=[C:39]3[C:38]4[N:37]=[C:36]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]6[O:7][C:6]([C:29]7[S:33][C:32]([CH3:34])=[N:31][CH:30]=7)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:10]=5)[CH:45]=[CH:44][C:43]=4[CH2:42][CH2:41][N:40]3[C:46]=2[CH:47]=[CH:48][CH:49]=1

Participants

9

Reactant 5

HCID 10340Sodium CarbonateHCID 11430Potassium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 90333549N-methyl-6-(N-methylmethylsulfonamido)-2-(2-methylthiazol-5-yl)-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 778457605-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)-2-(2-methylthiazol-5-yl)benzofuran-3-carboxamideYield 12.2%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

To a degassed solution of N-methyl-6-(N-methylmethylsulfonamido)-2-(2-methylthiazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (200 mg, 0.40 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (113 mg, 0.41 mmol), Na2CO3 (84 mg, 0.79 mmol), K2CO3 (109 mg, 0.79 mmol) in 1,4-dioxane (5 mL) and H2O (0.1 mL) were added Pd2(dba)3 (10 mg) and X-Phos (10 mg) under N2. Then the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O and dried over Na2SO4. After concentrated, the residue was purified by prep-HPLC to give the product (30 mg, yield: 12%). 1H-NMR (CDCl3, 400 MHz) δ 8.41 (s, 1H), 7.89 (s, 1H), 7.62˜7.68 (m, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.12˜7.20 (m, 2H), 6.74˜6.81 (m, 1H), 6.22 (d, J=4.0 Hz, 1H), 4.32 (t, J=6.4 Hz, 2H), 3.32 (s, 3H), 3.27˜3.31 (m, 2H), 3.02 (d, J=4.8 Hz, 3H), 2.75 (s, 3H), 2.74 (s, 3H). MS (M+H)+: 616.

Workup

  1. temperatureThe reaction mixture was cooled to RT
  2. filtrationfiltered
  3. washThe filtrate was washed with H2O
  4. dry with materialdried over Na2SO4
  5. concentrationAfter concentrated
  6. customthe residue was purified by prep-HPLC

Sources & evidence

ORD record
ord-6d1042efa5844e648c25d392ae966403
Source dataset
uspto-grants-2016_01
Patent number
US09243002B2

Reaction notes

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