Water → N-[5-[4-(5-{[4-(1-Methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide
Reaktionsgleichung
Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[CH3:35][O:36][C:37]1[C:42]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[CH3:33][CH:32]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:40]4[CH:41]=[C:42]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[C:37]([O:36][CH3:35])=[N:38][CH:39]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][CH:23]=2)[CH2:31][CH2:30]1)[CH3:34]Komponenten
Edukt 4
Produkt 1
Reagenzien, Katalysatoren, Lösungsmittel 2
Reaktionsbedingungen
- Temperatur
- 120 °C
Versuchsvorschrift
To a solution of 6-chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (200 mg, 0.400 mmol) and N-[2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide (171 mg, 0.520 mmol) in 1,4-dioxane (2 ml) was added chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (11.2 mg, 0.020 mmol), potassium phosphate tribasic (255 mg, 1.20 mmol) and water (0.2 ml). The reaction mixture was heated and stirred at 120° C. under microwave irradiation for 3 h. The reaction mixture was filtered through a silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous extracted with further dichloromethane (2×2 ml). The combined organics were concentrated under a stream of nitrogen and the residue dissolved in MeOH:DMSO (2 ml, 1:1, v/v) and purified by MDAP (method A) in 2 injections. The appropriate fractions were combined and concentrated and the residue dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and further purified by MDAP (method B). The appropriate fractions were basified to pH 7 with saturated sodium bicarbonate solution and extracted with dichloromethane (2×20 ml). The combined organics were dried (hydrophobic frit) and concentrated to give the title compound as a white solid (22 mg).
Aufarbeitung
- temperatureThe reaction mixture was heated
- filtrationThe reaction mixture was filtered through a silica SPE
- washeluted with methanol
- customThe solvent was removed in vacuo
- customthe residue partitioned between dichloromethane (5 ml) and water (5 ml)
- customThe layers were separated
- extractionthe aqueous extracted with further dichloromethane (2×2 ml)
- concentrationThe combined organics were concentrated under a stream of nitrogen
- dissolutionthe residue dissolved in MeOH
- customDMSO (2 ml, 1:1, v/v) and purified by MDAP (method A) in 2 injections
- concentrationconcentrated
- dissolutionthe residue dissolved in MeOH
- customDMSO (1 ml, 1:1, v/v) and further purified by MDAP (method B)
- extractionextracted with dichloromethane (2×20 ml)
- customThe combined organics were dried (hydrophobic frit)
- concentrationconcentrated
Quellen und Nachweise
- ORD-Eintrag
- ord-bc75891cff4046829dfb8f509ff8a35d
- Quelldatensatz
- uspto-grants-2013_11
- Patentnummer
- US08575162B2
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