2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 5-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-N-methyl-2-(4-methylisoxazol-3-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

HRID 595670Notes

Reaction equation

HRID 595670 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[C:33]([CH3:34])=[CH:32][O:31][N: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.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:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([C:29]7[C:33]([CH3:34])=[CH:32][O:31][N: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

6

Reactant 3

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 903336312-Chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridineHCID 90333823N-methyl-2-(4-methylisoxazol-3-yl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide

Product 1

HCID 778456695-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-N-methyl-2-(4-methylisoxazol-3-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamideYield 48.6%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
85 °C

Procedure

To a mixture of N-methyl-2-(4-methylisoxazol-3-yl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (60 mg, 0.12 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and K3PO4.3H2O (98 mg, 0.37 mmol) in dioxane/H2O (1.5 mL/0.5 mL) was added Pd2(dba)3 (8 mg, 0.008 mmol) and X-Phos (8 mg, 0.016 mmol) under N2. The mixture was stirred at 85° C. for 3 h. It was concentrated, diluted with water, extracted with EtOAc, and dried over Na2SO4. The residue was purified by prep-TLC (DCM:MeOH=60:1) to get the product (35 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 9.12 (d, J=3.6 Hz, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.28˜7.26 (m, 1H), 7.21˜7.12 (m, 2H), 6.85˜6.75 (m, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.46 (s, 3H), 3.33 (t, J=6.4 Hz, 2H), 3.03 (d, J=4.8 Hz, 3H), 2.60 (s, 3H), 2.40 (s, 3H). MS (M+H)+: 600.

Workup

  1. concentrationIt was concentrated
  2. additiondiluted with water
  3. extractionextracted with EtOAc
  4. dry with materialdried over Na2SO4
  5. customThe residue was purified by prep-TLC (DCM:MeOH=60:1)

Sources & evidence

ORD record
ord-d49f1e37f2a84aa095a4b7250fe402af
Source dataset
uspto-grants-2016_01
Patent number
US09243002B2

Reaction notes

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