2-Fluoro-N-methoxy-N-methylnicotinamide → Tert-butyl 4-(3-(2-fluoronicotinoyl)isoquinolin-1-yl)-1,4-diazepane-1-carboxylate

HRID 1929368Notes

Reaction equation

HRID 1929368 reaction equation
C([Li])CCC.Br[C:7]1[N:8]=[C:9]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[F:31][C:32]1[N:43]=[CH:42][CH:41]=[CH:40][C:33]=1[C:34](N(OC)C)=[O:35]>O1CCCC1>[F:31][C:32]1[N:43]=[CH:42][CH:41]=[CH:40][C:33]=1[C:34]([C:7]1[N:8]=[C:9]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19][CH2:18]2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:35]

Participants

5

Reactant 3

HCID 534170672-Fluoro-N-methoxy-N-methylnicotinamideHCID 57690659Tert-butyl 4-(3-bromoisoquinolin-1-yl)-1,4-diazepane-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 57690632Tert-butyl 4-(3-(2-fluoronicotinoyl)isoquinolin-1-yl)-1,4-diazepane-1-carboxylateYield 46%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

A 2.5M n-butyl lithium in tetrahydrofuran solution (0.16 ml, 0.40 mmol) was added dropwise to a solution of tert-butyl 4-(3-bromoisoquinolin-1-yl)-1,4-diazepane-1-carboxylate (155 mg, 0.38 mmol) in tetrahydrofuran (8 ml), cooled to −78° C. The reaction mixture was stirred at that temperature for 10 minutes. A solution of 2-fluoro-N-methoxy-N-methylnicotinamide (70 mg, 0.38 mmol) in tetrahydrofuran (3 ml) was added dropwise. The reaction mixture was allowed to warm up to room temperature and was stirred for 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted into ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a yellow solid (78 mg, 46% yield).

Workup

  1. temperatureto warm up to room temperature
  2. stirringwas stirred for 2 hours
  3. customThe reaction was quenched with a saturated aqueous solution of ammonium chloride
  4. extractionextracted into ethyl acetate
  5. dry with materialThe organic phase was dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified on silica gel by flash column chromatography

Sources & evidence

ORD record
ord-d17548e6cd5c45989c7022c4e895642b
Source dataset
uspto-grants-2012_05
Patent number
US08188071B2

Reaction notes

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