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

HRID 468740Notes

Reaction equation

HRID 468740 reaction equation
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

Participants

7

Reactant 4

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

Product 1

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

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
120 °C

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-b851f96256764e6792d0a4b5d772cd2a
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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