Diisopropylamine → 1-Benzyl-4-(2-chloroquinolin-3-yl)piperidin-4-ol

Temperature

-78 °C

A solution of n-butyllithium in hexane (1.6 M, 38.2 mL, 61.1 mmol) was added to a solution of diisopropylamine (8.6 mL, 61.1 mmol) in tetrahydrofuran (140 mL) at −78° C. under argon. After 1 h, a solution of 2-chloroquinoline (10.00 g, 61.1 mol) in tetrahydrofuran (30 mL) was added via syringe. After 1 h, a solution of 1-benzyl-4-piperidinone (11.3 mL, 61.1 mmol) was added, and the reaction stirred for an additional 40 min at −78° C., then allowed to warm to room temperature. The reaction was cooled to −20° C. and quenched with water. The reaction solution was extracted with ethyl acetate, and the organic phase washed with saturated brine and dried over magnesium sulfate. Chromatographic purification (silica gel, 0 to 10% {5% ammonium hydroxide/methanol} in methylene chloride gradient elution) gave the title compound, 11.3 g. MS 353 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 8.00 (d, J=8 Hz, 1H), 7.82 (d, J=8 Hz, 1H), 7.72 (dt, J=1, 10 Hz, 1H), 7.57 (dt, J=1, 8 Hz, 1H), 7.39-7.26 (m, 5H), 3.61 (s, 2H), 2.85 (d, J=11 Hz, 2H), 2.59 (t, J=12 Hz, 2H), 2.48 (dt, J=4, 13 Hz, 2H), 2.13 (d, J=12 Hz, 2H).

1. waitAfter 1 h
2. temperatureto warm to room temperature
3. temperatureThe reaction was cooled to −20° C.
4. customquenched with water
5. extractionThe reaction solution was extracted with ethyl acetate
6. washthe organic phase washed with saturated brine
7. dry with materialdried over magnesium sulfate
8. customChromatographic purification (silica gel, 0 to 10% {5% ammonium hydroxide/methanol} in methylene chloride gradient elution)

ORD record

ord-61673addd1e641e18d8f12477149acf5

Source dataset

uspto-grants-2011_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08039460B2