4-Bromo-3,5-dimethylpyridine → 8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

HRID 659062Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 659062
Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].[CH:10]1([CH2:13][O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26]C2C(Cl)=CN=CC=2Cl)[CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH:10]1([CH2:13][O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26][C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=2[CH3:9])[CH2:11][CH2:12]1

Komponenten

6

Edukt 3

HCID 223232464-Bromo-3,5-dimethylpyridineHCID 23676156Sodium t-butoxideHCID 248519118-(Cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

Produkt 1

HCID 236492908-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

A solution of 4-bromo-3,5-dimethylpyridine (1.16 g, 6.21 mmol) and degassed toluene (5 mL) was added to a mixture of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (1.94 g, 7.45 mmol, intermediate for Example 3), Pd2(dba)3, (0.28 g, 0.31 mmol), 2,2-dicyclohexylphosphorane triisopropylbiphenyl (0.59 g, 1.24 mmol), sodium tert-butoxide (1.20 g, 12.4 mmol), and degassed toluene (20 mL) under N2. The mixture was heated at 110° C. for 2 h, allowed to cool to rt, sonicated until the solids broke up, and then filtered through Celite with EtOAc (500 mL). The filtrate was concentrated, purified by silica gel chromatography (0→8% MeOH/CH2Cl2), and then repurified by reverse-phase HPLC (25→100% MeCN/H2O) to give 8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.43 (s, 1H), 8.42 (s, 2H), 7.89 (d, 1H), 7.03 (d, 1H), 4.54 (s, 1H), 3.91 (s, 3H), 3.85 (d, 2H), 2.15 (s, 6H), 1.28 (m, 1H), 0.47 (m, 2H), 0.28 (m, 2H); MS (ESI): 365.8.

Aufarbeitung

  1. customdegassed toluene (20 mL) under N2
  2. temperatureto cool to rt
  3. customsonicated until the solids
  4. filtrationfiltered through Celite with EtOAc (500 mL)
  5. concentrationThe filtrate was concentrated
  6. custompurified by silica gel chromatography (0→8% MeOH/CH2Cl2)
  7. customrepurified by reverse-phase HPLC (25→100% MeCN/H2O)

Quellen und Nachweise

ORD-Eintrag
ord-d55db3f8a10b43259ddee48ea28bc40f
Quelldatensatz
uspto-grants-2011_12
Patentnummer
US08080563B2

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