Sodium Hydroxide → 6-tert-Butyl-2-(3-{5-[6-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridazin-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one

HRID 449646

Reaktionsgleichung

Reaktionsgleichung von HRID 449646
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][C:14]([O:17][C:18]([CH3:24])([CH3:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C([O:28][CH2:29][C:30]1[C:35]([N:36]2[N:45]=[CH:44][C:43]3[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=3)[C:37]2=[O:51])=[CH:34][CH:33]=[CH:32][C:31]=1[B-](F)(F)F)(=O)C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>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.[Pd].CCCCO>[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[N:12]=[N:13][C:14]([O:17][C:18]([CH3:24])([CH3:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:16]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:30]=1[CH2:29][OH:28])[N:45]=[CH:44]2)([CH3:49])([CH3:47])[CH3:48]

Komponenten

9

Edukt 5

HCID 14798Sodium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 667429116-Chloro-4-[6-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridazin-3-ylamino]-2-methyl-2H-pyridazin-3-oneHCID 87134390potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate

Produkt 1

HCID 566559756-tert-Butyl-2-(3-{5-[6-(2-dimethylamino-1,1-dimethyl-ethoxy)-pyridazin-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-oneAusbeute 48,9 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumKatalysatorHCID 2631-ButanolLösungsmittelHCID 962WaterLösungsmittel2×

Reaktionsbedingungen

Temperatur
115 °C

Versuchsvorschrift

In a 15 mL microwave reaction vial was added 6-chloro-4-(6-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridazin-3-ylamino)-2-methylpyridazin-3(2H)-one (75 mg, 213 μmol, Eq: 1.00), n-BuOH (6 ml) and water (1.5 ml). To the mixture was added potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (101 mg, 213 μmol, Eq: 1.00) under argon. X-PHOS (10.6 μA, 31.9 μmol, Eq: 0.15) and potassium phosphate tribasic (99.3 mg, 468 μmol, Eq: 2.2) was added followed by bis(dibenzylideneacetone)palladium (9.17 mg, 15.9 μmol, Eq: 0.075). The tube was sealed under argon and heated in an oil bath at 115° C. for 3 hrs then stirred at room temperature overnight. To this mixture was added 100 mg NaOH in 1 mL distilled water. The mixture was warmed in an oil bath at 50° C. for 3 hrs then stirred at room temperature overnight. The crude reaction mixture was diluted with water (20 mL) and extracted with DCM (2×30 mL). The combined organic extracts were concentrated and absorbed onto silica gel. The crude material was purified by LC chromatography eluting with 0-5% (10% NH4OH in MeOH) in 1/1 EtOAc/heptane to afford 67 mg (47%) of the title compound as a pale yellow solid. Mp: 140-145° C. 1H NMR (300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 1.67 (s, 6H), 2.37 (s, 6H), 2.80 (s, 2H), 3.80 (t, J=6.2 Hz, 1H), 3.92 (s, 3H), 4.45 (d, J=6.2 Hz, 2H), 6.90 (d, J=9 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 7.43-7.65 (m, 5H), 8.20 (s, 1H), 8.28 (d, J=2.5, 1H), 8.55 (s, 1H). LCMS (ES): 643(M+H), RT=1.942 min.

Aufarbeitung

  1. customIn a 15 mL microwave reaction
  2. customThe tube was sealed under argon
  3. distillationdistilled water
  4. temperatureThe mixture was warmed in an oil bath at 50° C. for 3 hrs
  5. stirringthen stirred at room temperature overnight
  6. customThe crude reaction mixture
  7. extractionextracted with DCM (2×30 mL)
  8. concentrationThe combined organic extracts were concentrated
  9. customabsorbed onto silica gel
  10. customThe crude material was purified by LC chromatography
  11. washeluting with 0-5% (10% NH4OH in MeOH) in 1/1 EtOAc/heptane

Quellen und Nachweise

ORD-Eintrag
ord-b508a9e100ec41cb81d63fd527db9da0
Quelldatensatz
uspto-grants-2013_07
Patentnummer
US08481540B2

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