1-Bromo-3-chloropropane → 1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methoxy-1H-quinolin-2-one

HRID 2103293Notes

Reaction equation

HRID 2103293 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[CH:6]2.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19]Cl.C([O-])([O-])=O.[K+].[K+].[CH2:27]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]>CCOCC.CC#N.CCOC(C)=O>[CH2:27]([CH:31]1[CH2:36][CH2:35][N:34]([CH2:17][CH2:18][CH2:19][N:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:13])[CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]

Participants

9

Reactant 5

HCID 80061-Bromo-3-chloropropaneHCID 11430Potassium CarbonateHCID 24758Sodium hydrideHCID 2282682-Hydroxy-6-methoxyquinolineHCID 132838674-Butylpiperidine

Product 1

HCID 179561631-[3-(4-Butylpiperidin-1-yl)propyl]-6-methoxy-1H-quinolin-2-oneYield 44%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
45 °C

Procedure

A 4 mL vial was charged with 6-methoxy-1H-quinolin-2-one (0.032 g, 0.18 mmol) dry DMF (2 mL) and NaH (60% in oil, 8 mg, 0.20 mmol), thereafter the mixture was stirred at 45° C. for 45 min under a N2 atmosphere, followed by the addition of 1-bromo-3-chloropropane (18 μl, 0.18 mmol) and the mixture was shaken at 30° C. overnight. The reaction was then diluted with ether (25 mL) and washed with water (15 mL) and brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The oily residue was diluted with CH3CN (3 mL) and KI (0.080 g, 0.50 mmol), K2CO3 (0.070 g, 0.50 mmol) and 4-butylpiperidine (0.028 g, 0.20 mmol) were added. The mixture was shaken at 50° C. for 48 h and then diluted with EtOAc (25 mL) and washed with water (15 mL). The water phase was extracted (2×25 mL) and the combined organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep RP-HPLC to give the title compound (0.028 g, 44%). 1H NMR (CD3OD) δ 7.85 (d, J=9.6 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.26 (dd, J=2.8, 9.6 Hz, 1H), 7.19 (d J=2.8 Hz, 1H), 6.65 (d, J=9.6 Hz, 1H), 4.34 (t, J=7.2 Hz, 2H), 3.85 (s, 3H), 3.07-2.98 (m, 2H), 2.64-2.58 (m, 2H), 2.19-2.10 (m, 2H), 2.04-1.94 (m, 2H), 1.76-1.66 (m, 2H), 1.35-0.96 (m, 9H), 0.89 (t, J=6.8 Hz); 13C NMR (CD3OD) δ 162.7, 155.5, 140.1, 133.3, 122.3, 120.6, 120.1, 116.1, 110.5, 55.3, 55.0, 53.6, 40.5, 36.0, 35.2, 31.4, 28.8 24.4, 22.7, 13.2; HPLC-MS (ammonium acetate) [M+H]+=357.3.

Workup

  1. stirringthe mixture was shaken at 30° C. overnight
  2. washwashed with water (15 mL) and brine (15 mL)
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated under reduced pressure
  5. additionwere added
  6. stirringThe mixture was shaken at 50° C. for 48 h
  7. washwashed with water (15 mL)
  8. extractionThe water phase was extracted (2×25 mL)
  9. dry with materialthe combined organic phase was dried over Na2SO4
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by prep RP-HPLC

Sources & evidence

ORD record
ord-a1a55a65c3f1461cb4a0ad8fe78ebeb2
Source dataset
uspto-grants-2009_08
Patent number
US07576100B2

Reaction notes

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