3-Bromoanisole → HCID 13640222, compound

Temperature

-50 °C

To a stirred solution of 3-bromoanisole (12.83 g, 0.069 mol) in dry tetrahydrofuran (70 ml) at -50° C. under an atmosphere of nitrogen was added sec-butyllithium (1.3M in hexanes, 68.5 ml, 0.089 mol) dropwise, ensuring that the temperature in the reaction vessel did not rise above -50° C. After complete addition of the sec-butyllithium, a white precipitate formed, and the reaction was stirred for 1 hour at -50° C. N-Ethyl-4-(3-methoxyphenyl)piperidine (10.5 ml, 0.079 mol) in dry tetrahydrofuran (50 ml) was added dropwise at a rate to maintain the reaction temperature below -40° C., resulting in an orange solution. The reaction mixture was allowed to warm to -20° C. over 1.5 hours, and then to room temperature over a further 1 hour. After this time, the reaction mixture was quenched by the addition of saturated brine (21 ml) and water (30 ml). The quenched reaction was stirred for a further 30 minutes, and then the two phases separated, and the organic phase retained. The aqueous phase was extracted with dichloromethane (3×75 ml), and the two organics combined and washed with hydrochloric acid (1N, 2×50 ml). The aqueous layer was separated, basified with ammonium hydroxide to pH 10, and extracted with dichloromethane (3×40 ml). The dichloromethane extracts were concentrated to yield a thick oil, which was triturated in cold hexane until a solid was obtained. This crude solid was stirred in hot hexane, allowed to cool, and filtered to yield N-ethyl-4-hydroxy-4-(3-methoxyphenyl)piperidine (5.5 g, 33.7%) as a white solid. m.p.=86.7-91.1° C.

1. customdid not rise above -50° C
2. customa white precipitate formed
3. temperatureto maintain the reaction temperature below -40° C.
4. customresulting in an orange solution
5. temperatureto warm to -20° C. over 1.5 hours
6. waitto room temperature over a further 1 hour
7. customAfter this time, the reaction mixture was quenched by the addition of saturated brine (21 ml) and water (30 ml)
8. customThe quenched reaction
9. stirringwas stirred for a further 30 minutes
10. customthe two phases separated
11. extractionThe aqueous phase was extracted with dichloromethane (3×75 ml)
12. washwashed with hydrochloric acid (1N, 2×50 ml)
13. customThe aqueous layer was separated
14. extractionextracted with dichloromethane (3×40 ml)
15. concentrationThe dichloromethane extracts were concentrated
16. customto yield a thick oil, which
17. customwas triturated in cold hexane until a solid
18. customwas obtained
19. temperatureto cool
20. filtrationfiltered

ORD record

ord-25039f9b37834baabd1821748d0e259c

Source dataset

uspto-grants-1999_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05972962