Sodium Iodide → 1-{3-[3-(2-Cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]oct-8-yl]-propyl}-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one

HRID 1191528Notes

Reaction equation

HRID 1191528 reaction equation
Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[CH:18]1([CH2:21][O:22][CH2:23][CH:24]=[C:25]2[CH2:31][CH:30]3[NH:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[CH2:20][CH2:19]1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C.O>[CH:18]1([CH2:21][O:22][CH2:23][CH:24]=[C:25]2[CH2:26][CH:27]3[N:32]([CH2:2][CH2:3][CH2:4][N:5]4[C:14]5[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=5)[CH2:8][CH2:7][C:6]4=[O:17])[CH:30]([CH2:29][CH2:28]3)[CH2:31]2)[CH2:20][CH2:19]1

Participants

7

Reactant 4

HCID 5238Sodium IodideHCID 11430Potassium CarbonateHCID 179561691-(3-Chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-oneHCID 689104243-(2-Cyclopropylmethoxyethylidene)-8-aza-bicyclo[3.2.1]octane

Product 1

HCID 115320681-{3-[3-(2-Cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]oct-8-yl]-propyl}-6,7-difluoro-3,4-dihydro-1H-quinolin-2-oneYield 55%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 21891449acetonitrile N,N-dimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

A 4 ml vial was charged with 1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (78 mg, 0.30 mmol), 3-(2-cyclopropylmethoxyethylidene)-8-aza-bicyclo[3.2.1]octane (42 mg, 0.2 mmol), NaI (75 mg, 0.50 mmol), and K2CO3 (69 mg, 0.50 mmol) in CH3CN/DMF (1 ml, 50:50). The reaction was shaken at 50° C. for 3 days and the reaction was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography followed by flash column chromatography (SiO2; EtOAc/MeOH, 90:10) to yield the title compound as an oil (46 mg, 0.11 mmol, 53%). 1H NMR (CDCl3) δ 7.14 (dd, J=6.8, 12.4 Hz, 1H), 6.95-6.88 (m, 1H), 5.40 (t, J=6.6 Hz, 1H), 3.99-3.86 (m, 4H), 3.33-3.25 (m, 2H), 3.21 (d, J=6.8 Hz, 2H), 2.8 (t, J=6.8 Hz, 2H), 2.62-2.53 (m, 3H), 2.48 (t, J=6.8 Hz, 2H), 2.25 (br s, 1H), 1.95-1.74 (m, 5H), 1.58-1.36 (m, 2H), 1.08-0.96 (m, 1H), 0.56-0.44 (m, 2H), 0.22-0.08 (m, 2H); 13C NMR (CDCl3) δ 166.5, 146.2 (dd, J=13, 243 Hz), 142.4 (dd, J=13, 243), 134.2, 133.4 (br), 120.7 (br), 119.4 (br), 113.3 (d, J=18 Hz), 102.1 (br), 71.8, 63.0, 56.7, 56.4, 45.3, 38.0, 37.7, 30.9, 28.6, 23.9, 23.6, 23.0, 22.0, 7.7, 0.0; HPLC-MS (ammonium acetate) [M+H]+=398.21.

Workup

  1. extractionextracted with EtOAc
  2. washThe organic phase was washed with brine
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe oily residue was purified by ion-exchange column chromatography

Sources & evidence

ORD record
ord-d5d55c9ea5b845319ab12a2b74fafbd0
Source dataset
uspto-grants-2014_03
Patent number
US08680115B2

Reaction notes

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