Sodium Carbonate → 5-(11-fluoro-6-(hydroxymethyl)-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide

HRID 595559Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 595559
Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([CH2:19][OH:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:21]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([C:30]2[O:31][C:32]3[CH:42]=[C:41]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])[C:40](B4OC(C)(C)C(C)(C)O4)=[CH:39][C:33]=3[C:34]=2[C:35]([NH:37][CH3:38])=[O:36])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].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:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[N:21]=[C:2]([C:40]5[C:41]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])=[CH:42][C:32]6[O:31][C:30]([C:27]7[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=7)=[C:34]([C:35]([NH:37][CH3:38])=[O:36])[C:33]=6[CH:39]=5)[CH:3]=[CH:4][C:5]=4[O:18][CH:17]([CH2:19][OH:20])[N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1

Komponenten

8

Edukt 4

HCID 10340Sodium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86728254(2-chloro-11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-6-yl) methanolHCID 903331422-(6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide

Produkt 1

HCID 903410565-(11-fluoro-6-(hydroxymethyl)-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamideAusbeute 47 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
70 °C

Versuchsvorschrift

To a solution of (S or R)-(2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methanol (35 mg, 0.115 mmol), 2-(6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (50 mg, 0.097 mmol) and sodium carbonate (20 mg, 0.188 mmol) in 2 mL of 1,4-dioxane and 0.2 mL of water was added Pd2(dba)3 (10 mg) and X-Phos (10 mg) under nitrogen. The reaction mixture was heated at 70° C. for 16 hours and concentrated in vacuo to remove 1,4-dioxane. And then the residue was suspended in water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the product of (S or R)-5-(11-fluoro-6-(hydroxymethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(6-methoxypyridin-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 47%). 1H-NMR (CDCl3, 400 MHz) δ 8.72 (d, J=2.4 Hz, 1H), 8.14˜8.17 (m, 1H), 7.99 (s, 1H), 7.64 (s, 1H), 7.43˜7.48 (m, 2H), 7.14˜7.23 (m, 3H), 6.81˜6.86 (m, 2H), 6.42˜6.45 (m, 1H), 6.06 (brs, 1H), 4.01 (s, 3H), 3.98˜4.00 (m, 1H), 3.85˜3.88 (m, 1H), 3.37 (s, 3H), 2.96 (d, J=4.8 Hz, 3H), 2.72 (s, 3H), 2.27 (s, 1H). MS (M+H)+: 658.

Aufarbeitung

  1. concentrationconcentrated in vacuo
  2. customto remove 1,4-dioxane
  3. extractionextracted with EtOAc
  4. washThe combined organic phase was washed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue was purified by prep-HPLC

Quellen und Nachweise

ORD-Eintrag
ord-2905b0fd7d5a4e90b1f8097366b082ef
Quelldatensatz
uspto-grants-2016_01
Patentnummer
US09242998B2

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