2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 5-(5-(benzyloxy)-6-(4-fluoro-1H-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

HRID 1776825Notes

Reaction equation

HRID 1776825 reaction equation
[CH2:1]([O:8][C:9]1[C:10]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[C:22]([F:25])[CH:21]=[CH:20][CH:19]=3)=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:45]=[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[C:43](B4OC(C)(C)C(C)(C)O4)=[CH:42][C:36]=3[C:37]=2[C:38]([NH:40][CH3:41])=[O:39])=[CH:29][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:43]2[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])=[CH:45][C:35]3[O:34][C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[C:37]([C:38]([NH:40][CH3:41])=[O:39])[C:36]=3[CH:42]=2)=[N:11][C:10]=1[C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[C:22]([F:25])[CH:21]=[CH:20][CH:19]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 682394022-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamideHCID 867282372-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro-1H-indole

Product 1

HCID 712954695-(5-(benzyloxy)-6-(4-fluoro-1H-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamideYield 38.2%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
80 °C

Procedure

A mixture of 2-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro-1H-indole (160 mg, 0.454 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (228 mg, 0.454 mmol), K3PO4.H2O (362 mg, 1.362 mmol), Pd2(dba)3 (21 mg, 0.023 mmol) and X-Phos (22 mg, 0.046 mmol) in dioxane/H2O (2 mL/0.4 mL) was stirred at 80° C. for 2 hours under N2 atmosphere. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine (20 mL×3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using Prep-TLC (petroleum ether:EA=1:1) to provide 5-(5-(benzyloxy)-6-(4-fluoro-1H-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (120 mg, yield: 38.2%). 1H-NMR (CDCl3, 400 MHz) δ 9.97 (s, 1H), 7.93 (s, 1H), 7.88˜7.91 (m, 2H), 7.55 (s, 1H), 7.33˜7.48 (m, 7H), 6.69˜7.19 (m, 5H), 6.65˜6.69 (m, 1H), 5.83 (d, J=4.4 Hz, 1H), 5.31 (s, 2H), 3.08 (s, 3H), 2.91 (d, J=4.8 Hz, 3H), 2.75 (s, 3H). MS (M+H)+: 693.

Workup

  1. extractionextracted with ethyl acetate (30 mL×3)
  2. washThe organic layer was washed with brine (20 mL×3)
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated in vacuo
  5. customThe resulting residue was purified

Sources & evidence

ORD record
ord-9670ec5b789d46feb5407603904cd472
Source dataset
uspto-grants-2016_02
Patent number
US09265773B2

Reaction notes

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