Methyl iodide → (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one

温度

-78 °C

A solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one (Example 71, Step A) (140.34 g, 298 mmol) in anhydrous THF (994 mL) was degassed by bubbling argon through the solution for 20 minutes while it cooled to −78° C. Iodomethane (23.32 mL, 373 mmol) was added followed by the addition of LHMDS (328 mL, 328 mmol) over 15 minutes. The reaction mixture was stirred for 15 minutes at −78° C. and then the reaction was removed from the cold bath and stirred at rt for 12 hours. The reaction was quenched by the addition of sat. aq. NH4Cl and the layers were separated. The aqueous layer was extracted with EtOAc (2×500 mL) and the organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide an orange oil. Purification (wet loaded with small amount of DCM) using the Combiflash Companion XL (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) with a 1.5 kg SiO2 column and eluting with 4 L each of 15-20-25-30-35% EtOAc/hexanes provided the title compound as a thick very pale yellow oil and a 3.7:1 mixture of C-3 diastereomers.

1. customby bubbling argon through the solution for 20 minutes while it
2. customthe reaction was removed from the cold bath
3. stirringstirred at rt for 12 hours
4. customThe reaction was quenched by the addition of sat. aq. NH4Cl
5. customthe layers were separated
6. extractionThe aqueous layer was extracted with EtOAc (2×500 mL)
7. washwashed with sat. aq. NaCl solution
8. dry with materialdried (MgSO4)
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customto provide an orange oil
12. customPurification (wet loaded with small amount of DCM)
13. washeluting with 4 L each of 15-20-25-30-35% EtOAc/hexanes

ORDレコード

ord-c4b4b2a177f6438eb26675f76bb564e8

出典データセット

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09296736B2