Dimethylformamide → 6-(6-(dimethylamino)pyridin-3-yl)-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide

HRID 85487Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 85487
Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.Br[C:29]1[CH:30]=[C:31](C(OC)=O)[C:32]2[C:33](C=O)=[N:34]NC=2C=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:50][N:51](C=O)[CH3:52]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:50][N:51]([CH3:52])[C:33]1[N:34]=[CH:29][C:30]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=2)=[CH:31][CH:32]=1

Komponenten

7

Edukt 4

HCID 6228DimethylformamideHCID 10340Sodium CarbonateHCID 545962226-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamideHCID 178497028HCID 178497028, Verbindung

Produkt 1

HCID 545963006-(6-(dimethylamino)pyridin-3-yl)-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418476HCID 178418476, VerbindungKatalysatorHCID 962WaterLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (300 mg, 0.696 mmol) in DMF (30 mL) was added 6-(dimethylamino)pyridin-3-yl-3-boronic acid, 1 (127 mg, 0.765 mmol) followed by sodium carbonate (184.4 mg, 1.74 mmol) dissolved in water (3 mL) and degassed with argon for 1 h. Then PdCl2(PPh3)2 (48.8 mg, 0.069 mmol) was added and again degassed with argon for 15 min and stirred at 110° C. for 4 h. The reaction mixture was filtered through Celite pad and washed with ethyl acetate (50 mL). The filtrate was diluted with water and extracted with ethyl acetate (4×90 mL). The combined organic layers were separated and washed with cold water (2×50 mL), brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (450 mg). The crude compound was purified by silica gel chromatography (eluent: 5% MeOH: DCM) to afford 100 mg of desired product which was triturated with hexane and the solid was filtered and dried to afford the title compound as an off white solid (100 mg, 30%). 1H NMR (DMSO-d6, 400 MHz): δ 1.559 (d, J=6.8 Hz, 6H), 2.102 (s, 3H), 2.403 (s, 3H), 2.539 (s, 3H), 3.125 (s, 6H), 4.616 (s, 2H), 4.754-4.820 (m, 1H), 5.893 (s, 1H), 6.557 (d, J=8.8 Hz, 1H), 7.313 (s, 1H), 7.401 (d, J=5.2 Hz, 1H), 7.448 (s, 1H), 7.707 (d, J=8.8 Hz, 1H), 8.438 (s, 1H), 11.502 (brs, 1H). 1H NMR (D2O Ex in DMSO, 400 MHz): δ 1.559 (d, J=6.8 Hz, 6H), 2.115 (s, 3H), 2.408 (s, 3H), 2.538 (s, 3H), 3.124 (s, 6H), 4.616 (s, 2H), 4.754-4.820 (m, 1H), 5.899 (s, 1H), 6.557 (d, J=8.8 Hz, 1H), 7.318 (s, 1H), 7.450 (s, 1H), 7.718 (d, J=8.8 Hz, 1H), 8.438 (s, 1H). LCMS (ES+): 473.19.

Aufarbeitung

  1. customdegassed with argon for 1 h
  2. customagain degassed with argon for 15 min
  3. filtrationThe reaction mixture was filtered through Celite pad
  4. washwashed with ethyl acetate (50 mL)
  5. additionThe filtrate was diluted with water
  6. extractionextracted with ethyl acetate (4×90 mL)
  7. customThe combined organic layers were separated
  8. washwashed with cold water (2×50 mL), brine solution (50 mL)
  9. dry with materialdried over anhydrous Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto afford the crude product (450 mg)
  13. customThe crude compound was purified by silica gel chromatography (eluent: 5% MeOH: DCM)

Quellen und Nachweise

ORD-Eintrag
ord-495cdde9ddcb49949b5d9cc9fdf83e54
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08846935B2

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