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

HRID 1094524Notes

Reaction equation

HRID 1094524 reaction equation
[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]

Participants

9

Reactant 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

Product 1

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

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-b080f7b1a56d4969a4be25af4e28e01c
Source dataset
uspto-grants-2012_03
Patent number
US08133886B2

Reaction notes

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