4-Methyloxybenzyl chloride → 1-Tert-butyl 3-ethyl 3-(4-methylbenzyl)piperidine-1,3-dicarboxylate

Temperature

0 °C

A solution of the product from STEP 1 (5.0 g, 19.5 mmol) in 20 ml THF was added to a solution of lithium diisopropylamine (11.7 ml, 23.4 mmol, 2M solution) in 25 ml THF dropwise at −20° C. The resulting mixture was stirred at 0° C. for 15 min and allowed to warm to room temperature. After 1 h, the reaction was cooled to −20° C. and treated, dropwise, with a solution of 4-methoxy-benzyl chloride (3.1 g, 19.5 mmol) in 20 ml THF. The resulting mixture was stirred at −10° C. for 1 h, and warmed to 35° C. After 1 h, the reaction was quenched with 25 ml saturated aqueous NH4Cl solution. The product was extracted with ethyl acetate (2×100 ml). The aqueous layer was extracted with ethyl acetate. The combined layers were were washed with H2O, brine, and then dried with Na2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/4) to yield a viscous oil in 5.2 g. The 1H NMR spectrum of the product was consistent for the proposed structure.

1. temperatureto warm to room temperature
2. waitAfter 1 h
3. temperaturethe reaction was cooled to −20° C.
4. additiontreated
5. stirringThe resulting mixture was stirred at −10° C. for 1 h
6. temperaturewarmed to 35° C
7. waitAfter 1 h
8. customthe reaction was quenched with 25 ml saturated aqueous NH4Cl solution
9. extractionThe product was extracted with ethyl acetate (2×100 ml)
10. extractionThe aqueous layer was extracted with ethyl acetate
11. washThe combined layers were were washed with H2O, brine
12. dry with materialdried with Na2SO4
13. concentrationconcentrated
14. customThe residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/4)
15. customto yield a viscous oil in 5.2 g

ORD record

ord-c7a21b5a1dbc47da869f2b4224da2793

Source dataset

uspto-grants-2003_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06531494B1