p-Bromochlorobenzene → 4-(4-Chlorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol

Temperature

-78 °C

To 1-bromo-4-chlorobenzene (397 mg, 2.07 mmol) in tetrahydrofuran (10 mL), at −78° C., was added n-butyllithium (0.91 mL of a 2.5 M solution in hexanes, 2.3 mmol) dropwise. After 0.5 h, a solution of the ketone (500 mg, 2.28 mmol) from Step B above in tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1.5 h and then warmed to 0° C. After 1 h, the reaction mixture was quenched with saturated ammonium chloride (5 mL) and warmed to ambient temperature. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated ammonium chloride (20 mL), water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography (5% ethyl acetate/methylene chloride to ethyl acetate) gave 4-(4-chlorophenyl)-1-(3-methoxybenzyl)piperidin-4-ol (370 mg, 53%) as a colorless oil: 1H NMR (DMSO-d6, 500 MHz) δ 7.50 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.24-7.21 (m, 1H), 6.90-6.89 (m, 2H), 6.81-6.79 (m, 1H), 4.87 (s, 1H), 3.74 (s, 3H), 3.47 (s, 2H), 2.61-2.59 (m, 2H), 2.43-2.38 (m, 2H), 1.94-1.87 (m, 2H), 1.57-1.54 (m, 2H).

1. temperaturewarmed to 0° C
2. waitAfter 1 h
3. customthe reaction mixture was quenched with saturated ammonium chloride (5 mL)
4. temperaturewarmed to ambient temperature
5. additionThe mixture was diluted with ethyl acetate (50 mL)
6. washwashed with saturated ammonium chloride (20 mL), water (20 mL), brine (20 mL)
7. dry with materialdried over sodium sulfate
8. concentrationconcentrated in vacuo
9. customPurification by silica gel chromatography (5% ethyl acetate/methylene chloride to ethyl acetate)

ORD record

ord-7d8f8a67716f4b749376ef8648543f03

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09045468B2