Potassium Phosphate, Tribasic → 2-(bicyclo[3.1.0]hexan-1-yl)-5-(11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

HRID 595585Notes

Reaction equation

HRID 595585 reaction equation
[C:1]12([C:7]3[O:8][C:9]4[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[C:17](B5OC(C)(C)C(C)(C)O5)=[CH:16][C:10]=4[C:11]=3[C:12]([NH:14][CH3:15])=[O:13])[CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.Cl[C:36]1[CH:37]=[CH:38][C:39]2[O:52][CH2:51][N:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[C:47]([F:50])[C:48]=4[CH:49]=[C:41]3[C:40]=2[N:53]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:1]12([C:7]3[O:8][C:9]4[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:22])=[O:23])[C:17]([C:36]5[CH:37]=[CH:38][C:39]6[O:52][CH2:51][N:42]7[C:43]8[CH:44]=[CH:45][CH:46]=[C:47]([F:50])[C:48]=8[CH:49]=[C:41]7[C:40]=6[N:53]=5)=[CH:16][C:10]=4[C:11]=3[C:12]([NH:14][CH3:15])=[O:13])[CH2:6][CH:5]1[CH2:4][CH2:3][CH2:2]2

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 867283052-chloro-11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indoleHCID 903335532-(bicyclo[3.1.0]hexan-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide

Product 1

HCID 778460002-(bicyclo[3.1.0]hexan-1-yl)-5-(11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamideYield 16.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a degassed solution of 2-(bicyclo[3.1.0]hexan-1-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.20 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (67 mg, 0.24 mmol), K3PO4 (109 mg, 0.41 mmol) in 1,4-Dioxane (5 mL) and H2O (0.5 ml) was added Pd(dba)3 (5 mg), X-Phos (5 mg) under N2, then the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O, brine, extracted with DCM, and dried over Na2SO4. After concentration, the residue was purified by prep-HPLC to give the product of 2-(bicyclo[3.1.0]hexan-1-yl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 16%). 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.55 (s, 1H), 7.46 (s, 2H), 7.21 (s, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.86 (q, J=8.0 Hz, 1H), 6.17 (d, J=4.0 Hz, 1H), 5.60 (s, 2H), 3.38 (s, 3H), 3.05 (d, J=4.8 Hz, 3H), 2.67 (s, 3H), 2.14˜2.22 (m, 2H), 2.11˜2.16 (m, 2H), 2.01˜2.09 (m, 2H), 1.91˜1.98 (m, 1H), 1.84 (d, J=4.0 Hz, 2H). MS (M+H)+: 601.

Workup

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

Sources & evidence

ORD record
ord-4f8c5b1bf43a41c498e56a0ca1110b7a
Source dataset
uspto-grants-2016_01
Patent number
US09242998B2

Reaction notes

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