19% |
Stage #1: 6-chloroquinolin-2(1H)-oney With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.75h; Inert atmosphere;
Stage #2: 1.3-chlorobromopropane In N,N-dimethyl-formamide; mineral oil at 20℃;
Stage #3: 4-n-butylpiperidine With potassium carbonate; potassium iodide In acetonitrile at 50℃; for 24h; |
1 1 -[3-(4-l3utylpiperidin-1 -yl)propyl]-6-chloro-1H-quinolin-2-one (107EH38-A)
A 4 mE vial was charged with 6-chloro-1H-quinolin-2-one (107EH35) (0.085 g, 0.47 mmol), dry DMF (3 mE) andNaH (60% in oil, 0.023 g, 0.56 mmol) and the mixture wasstirred at it for 45 mm under a N2 atmosphere. Thereafter,-bromo-3-chloropropane (18 pi, 0.18 mmol) was added andmixture was shaken at it overnight, the reaction dilutedwith ether (25 mE) and washed with water (15 mE). Theether phase was washed with brine (15 mE), dried overNa2SO4, concentrated under reduced pressure. The oilyresidue was diluted with dry CH3CN (2 mE) and KI (0.1701.0 mmol), K2C03 (0.140 g, 1.0 mmol) and 4-butylpip-eridine (0.07 1 g, 0.50 mmol) were added. The mixture wasshaken at 50° C. for 24 h and then diluted with EtOAc (25mE) and washed with water (15 mE). The water phase wasextracted (2x25 mE) and the combined organic phases weredried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep RP-HPEC to give thetitle compound (32 mg, 89 tmol, 19%). ‘H NMR (CD3OD)7.80 (d, J=9.2 Hz, 1H), 7.66 (brs, 1H), 7.60-7.5 1 (m, 2H),6.65 (d, J=9.6 Hz, 1H), 5.30 (t, J=7.6 Hz, 2H), 3.09-2.95 (m,2H), 2.68-2.57 (m, 2H), 2.24-2.06 (m 2H), 2.00-1.90 (m,2H), 1.75-1.64 (m, 2H), 1.32-1.12 (m, 9H), 0.84 (t, 6.4 Hz,3H); ‘3C NMR (CD3OD) ö 162.6, 139.2, 137.4, 130.8,128.0, 127.8, 122.4, 121.5, 116.3, 55.0, 53.3, 40.3, 35.7,34.8, 31.0, 28.6, 23.9, 22.5, 13.0; HPEC-MS (ammoniumacetate) [M+H]=361 .3. |