Toluene → (4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester

HRID 884763Notes

Reaction equation

HRID 884763 reaction equation
[C:1]([O:5][C:6](=[O:36])[NH:7][N:8]1[C:17]([CH3:18])=[C:16]([C:19](=[O:33])[NH:20][C@@H:21]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:15]2[C:10](=[C:11]([F:34])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:35])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[OH-].[K+].I[CH2:47][CH2:48][CH2:49][F:50]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[C:1]([O:5][C:6](=[O:36])[N:7]([N:8]1[C:17]([CH3:18])=[C:16]([C:19](=[O:33])[NH:20][C@@H:21]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:15]2[C:10](=[C:11]([F:34])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:35])[CH2:47][CH2:48][CH2:49][F:50])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 1140TolueneHCID 14797Potassium HydroxideHCID 128991281-Iodo-3-fluoropropaneHCID 67297917(4-{[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester

Product 1

HCID 67303998(4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-(3-fluoro-propyl)-carbamic acid tert-butyl esterYield 135.6%

Reagents, catalysts & solvents 1

HCID 74236Tetrabutylammonium BromideCatalyst

Conditions

Temperature
50 °C

Procedure

To (4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (0.5000 g, 1.005 mmol; prepared as described in example 8) and tetra-N-butylammonium bromide (0.340 g, 1.05 mmol) in toluene (10 mL, 90 mmol) was added potassium hydroxide (84.6 mg, 1.51 mmol) (powdered). The reaction was stirred at 50° C. for 10 minutes. 1-Iodo-3-fluoropropane (0.525 g, 2.79 mmol) was added and the reaction mixture was stirred for 1 hour at 50° C. The temperature was raised to 80° C. and the reaction mixture was stirred for another for 2 hours. The reaction mixture was cooled to room temperature and washed with 50 ml of water, dried over MgSO4 and was concentrated in vacuo to give 0.76 g (4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-(3-fluoro-propyl)-carbamic acid tert-butyl ester as an oil. The Boc-protection group was removed analogously to the method described in example 6 with trifluoroacetic acid in 1,2-dichloroethane to give the title compound.

Workup

  1. stirringthe reaction mixture was stirred for 1 hour at 50° C
  2. temperatureThe temperature was raised to 80° C.
  3. stirringthe reaction mixture was stirred for another for 2 hours
  4. temperatureThe reaction mixture was cooled to room temperature
  5. washwashed with 50 ml of water
  6. dry with materialdried over MgSO4
  7. concentrationwas concentrated in vacuo

Sources & evidence

ORD record
ord-f9b3ddf09a4c4a07afe58c114804b27d
Source dataset
uspto-grants-2012_08
Patent number
US08242134B2

Reaction notes

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