Cyclohexane → HCID 13640221, compound

Temperature

-50 °C

A suitable dry reaction vessel having a mechanical stirrer, low temperature thermometer and addition funnel was charged with 250 g (1.34 mol) of m-bromoanisole (Aldrich Chemical Company, Milwaukee, Wis.) in 675 ml of dry tetrahydrofuran and the solution was cooled under nitrogen to -50° C. to -55° C. in a dry ice/acetone bath. A solution of 1357 ml. of sec.-butyllithium in cyclohexane (1.71 mol) was added dropwise to the reaction mixture at such a rate so that the temperature did not rise above -50° C. The resulting white suspension was stirred at -50° C. for 1 hour followed by the addition of 174.2 g (1.54 mol) of 1-methyl-4-piperidone (Aldrich Chemical Company) in 440 ml of dry tetrahydrofuran so as to maintain the reaction temperature below -40° C. When the addition was complete the temperature was allowed to rise to approximately -20° C. over approximately 11/2 hours and then to room temperature over a 1 hour period. Residual sec.-butyllithium was quenched by the addition of 350 ml of saturated sodium chloride solution followed by the addition of 525 ml of water. The aqueous phase was separated and extracted twice with 350 ml portions of methylene chloride. The combined organic extracts were extracted in two portions, each with 1250 ml of 1N hydrochloric acid. The separated aqueous extracts were made basic (pH=10) with 28 percent ammonium hydroxide and extracted 3 times with 350 ml portions of methylene chloride. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was slurried in 1000 ml of hot hexane and the slurry was cooled and filtered. The isolated crystalline product was dried in a vacuum oven to provide 225.6 g of 98% pure product.

1. customA suitable dry
2. customreaction vessel
3. additionlow temperature thermometer and addition funnel
4. temperaturethe solution was cooled under nitrogen to -50° C. to -55° C. in a dry ice/acetone bath
5. customdid not rise above -50° C
6. temperatureto maintain the reaction temperature below -40° C
7. additionWhen the addition
8. customto rise to approximately -20° C. over approximately 11
9. custom2 hours
10. waitto room temperature over a 1 hour period
11. customResidual sec.-butyllithium was quenched by the addition of 350 ml of saturated sodium chloride solution
12. additionfollowed by the addition of 525 ml of water
13. customThe aqueous phase was separated
14. extractionextracted twice with 350 ml portions of methylene chloride
15. extractionThe combined organic extracts were extracted in two portions
16. extractionextracted 3 times with 350 ml portions of methylene chloride
17. dry with materialThe organic phase was dried over anhydrous sodium sulfate
18. customthe solvent was evaporated in vacuo
19. temperaturethe slurry was cooled
20. filtrationfiltered
21. customThe isolated crystalline product was dried in a vacuum oven

ORD record

ord-d0c291165acd4dc78166620f59a31136

Source dataset

uspto-grants-1986_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04581456