Cesium carbonate → [1-(3-fluoro-4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanone

HRID 1928657Notes

Reaction equation

HRID 1928657 reaction equation
Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH3:15])=[C:4]([F:18])[CH:3]=1.[N:19]1([C:25]([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C)C=O.[Cu](I)I>[F:18][C:4]1[CH:3]=[C:2]([N:29]2[CH:28]=[C:27]([C:25]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:26])[CH:31]=[N:30]2)[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH3:15]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 20784942Morpholino(1H-pyrazol-4-yl)methanoneHCID 59541739(2R)-1-[3-(4-bromo-2-fluorophenoxy)propyl]-2-methylpyrrolidine

Product 1

HCID 42610352[1-(3-fluoro-4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanoneYield 36%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of (2R)-1-[3-(4-bromo-2-fluorophenoxy)propyl]-2-methylpyrrolidine obtained in Example 62-(2) (0.72 g) and morpholin-4-yl(1H-pyrazol-4-yl)methanone (0.45 g) in N,N-dimethylformamide (3 mL), cesium carbonate (1.6 g), copper iodide (0.1 g) and (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (0.36 mL) were added and the mixture was heated to 130° C., at which it was stirred for 6 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=11:1 to 3:1) and NH-type silica gel column chromatography (eluting solvent: chloroform:methanol=10:0 to 100:1) to give the titled compound (0.34 g, 36%) as a colorless solid.

Workup

  1. additionwere added
  2. temperatureThe reaction mixture was cooled to room temperature
  3. filtrationfiltered
  4. customto remove insoluble materials
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customThe resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=11:1 to 3:1) and NH-type silica gel column chromatography (eluting solvent: chloroform:methanol=10:0 to 100:1)

Sources & evidence

ORD record
ord-766cb27d95844bfc99573b9393ae67f4
Source dataset
uspto-grants-2012_05
Patent number
US08183387B2

Reaction notes

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