Methyl iodide → 1-tert-Butyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate

Temperature

-30 °C

To a flame-dried round bottom flask under Argon atmosphere was added THF (100 mL), then it was cooled to −30° C. To this cold solvent were added n-butyllithium (40.1 ml, 64.1 mmol), and diisopropylamine (10.80 ml, 76 mmol) drop wise. The resultant solution was stirred at −25° C. for 1 hour. To the above solution 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (15 g, 58.3 mmol) in THF (20 mL) was added drop wise at −78° C. (maintain temperature <−70° C.). After the addition, the reaction was stirred at −70° C. for 1 h, and then methyl iodide (4.74 mL, 76 mmol) was added drop wise. This reaction mixture was stirred at same temperature for 1 h, then slowly warmed to RT and stirred for 16 h. The reaction mixture was quenched with sat. aq. NH4Cl (50 mL), extracted with EtOAc (2×200 mL), the combined organics extracts was washed with sat. NH4Cl (100 mL), brine (50 mL), dried (Na2SO4) and concentrated to get crude compound. The crude residue was purified by ELSD ISCO on 120 g silica column, eluted the compound around 20% ethyl acetate in hexanes, the pure fractions were collected and concentrated to give desired product 1-tert-butyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (15.14 g, 52.5 mmol, 90% yield) as a colorless oil. Anal. Calcd. for C14H25NO4 m/z 271.3, found: 172.2 (M-Boc+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 4.13 (q, J=7.0 Hz, 2 H), 3.82 (d, J=13.5 Hz, 1 H), 3.46-3.38 (m, 1 H), 3.32-3.19 (m, 1 H) 3.13 (d, J=13.2 Hz, 1 H) 2.07-1.97 (m, 1 H) 1.60-1.50 (m, 2 H) 1.48-1.40 (m, 10 H), 1.25 (t, J=7.15 Hz, 3 H), 1.15 (s, 3 H)

1. temperature(maintain temperature <−70° C.)
2. additionAfter the addition
3. stirringThis reaction mixture was stirred at same temperature for 1 h
4. temperatureslowly warmed to RT
5. stirringstirred for 16 h
6. customThe reaction mixture was quenched with sat. aq. NH4Cl (50 mL)
7. extractionextracted with EtOAc (2×200 mL)
8. washthe combined organics extracts was washed with sat. NH4Cl (100 mL), brine (50 mL)
9. dry with materialdried (Na2SO4)
10. concentrationconcentrated
11. customto get crude compound
12. customThe crude residue was purified by ELSD ISCO on 120 g silica column
13. washeluted the compound around 20% ethyl acetate in hexanes
14. customthe pure fractions were collected
15. concentrationconcentrated

ORD record

ord-2d7aae89c780473d827081ff5816d694

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08815909B2