Acetamide → 6-(6-Acetylamino-pyrimidin-4-yloxy)-isoquinoline-1-carboxylic acid [5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-amide

HRID 1094524Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1094524
[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][C:32]4[CH:37]=[C:36](Cl)[N:35]=[CH:34][N:33]=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:45]([NH2:48])(=[O:47])[CH3:46].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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].CCOC(C)=O.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][C:32]4[CH:37]=[C:36]([NH:48][C:45](=[O:47])[CH3:46])[N:35]=[CH:34][N:33]=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]

Komponenten

9

Edukt 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866386216-(6-Chloro-pyrimidin-4-yloxy)-isoquinoline-1-carboxylic acid [5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-amide

Produkt 1

HCID 236529306-(6-Acetylamino-pyrimidin-4-yloxy)-isoquinoline-1-carboxylic acid [5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-amide

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
70 °C

Versuchsvorschrift

150.0 mg (0.28 mMol) 6-(6-Chloro-pyrimidin-4-yloxy)-isoquinoline-1-carboxylic acid [5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-amide is dissolved in 5 ml dioxane. After addition of 131 mg Cs2CO3 (>99%, Fluka 20959; 0.40 mMol), 25 mg (0.43 mMol) acetamide, 20 mg Xantphos (Aldrich 52, 646-0; 0.034 mMol) and 10.5 mg Pd2(dba)3 (Aldrich 32, 877-4; 0.011 mMol) the reaction mixture is heated to 70° C. for 20 h. It is cooled to rt again and worked up by addition of H2O and EtOAc. The phases are separated and the aq. layer is repeatedly extracted with EtOAc. Combined organic extracts are washed with brine, dried and concentrated. The residual crude product is purified by flash chromatography (combi-flash: 40 g column, hexanes/EtOAc; gradient 0-50% EtOAc) to give the title compound as a yellow solid: MS: [M+1]+=553; 1H MNR (CDCl3): δ ppm 10.70 (s, 1H), 9.43 (d, 1H), 8.44 (s, 1H), 8.38 (d, 1H), 8.15 (bs, HN), 7.84 (s, 1H), 7.74 (d, 1H), 7.63 (s, 1H), 7.52-7.48 (m, 3H), 7.05 (d, 2H), 6.87 (s, 1H), 5.29 (s, 1H), 3.88 (s, 3H), 2.25 (s, 3H), 1.41 (s, 9H).

Aufarbeitung

  1. temperatureIt is cooled to rt again
  2. customThe phases are separated
  3. extractionthe aq. layer is repeatedly extracted with EtOAc
  4. washCombined organic extracts are washed with brine
  5. customdried
  6. concentrationconcentrated
  7. customThe residual crude product is purified by flash chromatography (combi-flash: 40 g column, hexanes/EtOAc; gradient 0-50% EtOAc)

Quellen und Nachweise

ORD-Eintrag
ord-b080f7b1a56d4969a4be25af4e28e01c
Quelldatensatz
uspto-grants-2012_03
Patentnummer
US08133886B2

Notizen zur Reaktion

Wird geladen…