Cesium carbonate → N-(7-(4-methylpiperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 1502258Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1502258
Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C(=O)C>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH2:21][CH2:20]1

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 531671-MethylpiperazineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 67974626N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide

Produkt 1

HCID 57410481N-(7-(4-methylpiperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamideAusbeute 41 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 167845palladium(II) acetateKatalysatorHCID 31374DimethylacetamideLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (131.4 mg, 0.4513 mmol), 1-methyl-piperazine (0.11 mL, 0.99 mmol), palladium (II) acetate (10.4 mg, 0.0463 mmol), XPhos (35.4 mg, 0.0742 mmol), and cesium carbonate (462 mg, 1.42 mmol) was added N,N-dimethylacetamide (4 mL). The reaction mixture was then stirred in a sealed vial at 120° C. for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and half-saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 10-30% methanol in dichloromethane) to yield 57.2 mg (41%) of N-(7-(4-methylpiperazin-1-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=2.744, M+H=311.1, method=E; 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.42 (s, 1H), 8.14 (s, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.44 (dd, J=9.1, 2.5 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 3.36-3.25 (m, 4H), 2.69-2.58 (m, 4H), 2.39 (s, 3H), 1.58 (m, 1H), 1.18-1.08 (m, 2H), 0.94-0.85 (m, 2H).

Aufarbeitung

  1. temperatureThe reaction mixture was then cooled to room temperature
  2. custompartitioned between ethyl acetate and half-saturated aqueous NaHCO3
  3. dry with materialThe organic layer was dried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customThe crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 10-30% methanol in dichloromethane)

Quellen und Nachweise

ORD-Eintrag
ord-b4ee52fd3a5a40609ab3e6f409257ed0
Quelldatensatz
uspto-grants-2015_12
Patentnummer
US09206175B2

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