Sodium Iodide → 1-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one

HRID 1191525Notes

Reaction equation

HRID 1191525 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][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]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][CH:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=4)[CH2:8][CH2:7][C:6]3=[O:17])[CH2:25][CH2:24]2)[CH2:19][CH2:20]1

Participants

7

Reactant 4

HCID 5238Sodium IodideHCID 11430Potassium CarbonateHCID 171780104-(Cyclopropylmethoxy)piperidineHCID 179561691-(3-Chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one

Product 1

HCID 115381241-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-oneYield 81.5%

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), 4-cyclopropylmethoxypiperidine (145LH49) (42 mg, 0.27 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) to yield the title compound as an oil (83 mg, 0.22 mmol, 81%). 1H NMR (CDCl3) δ 6.90 (dd, J=6.8, 12.0 Hz, 1H), 6.82-6.75 (m, 1H), 3.73 (t, J=7.2 Hz, 2H), 3.22-3.13 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.69-2.54 (m, 4H), 2.47-2.41 (m, 2H), 2.23-2.17 (m, 2H), 2.01-1.91 (m, 2H), 1.78-1.58 (m, 4H), 1.52-1.40 (m, 2H), 0.94-0.82 (m, 1H), 0.44-0.28 (m, 2H), 0.06 (−) 0.03 (m, 2H); 13C NMR (CDCl3) δ 166.4, 146.1 (dd, J=13, 243 Hz), 142.3 (dd, J=13, 243 Hz), 133.3 (dd, J=3, 8 Hz), 119.4 (dd, J=2, 5 Hz), 113.3 (d, J=18 Hz), 102.0 (d, J=22 Hz), 71.5 (br), 69.5, 52.2, 48.3, 38.0, 28.6, 28.2, 21.9, 21.7, 7.9, 0.0; HPLC-MS (ammonium acetate) [M+H]+=379.29.

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-2c17174b7e46426a98e08c835881e2a2
Source dataset
uspto-grants-2014_03
Patent number
US08680115B2

Reaction notes

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