Sodium hydride → (S)-Ethyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(5-chloropyridin-2-yl)-6-oxopiperidin-1-yl)butanoate

Temperature

0 °C

To an ice-cooled solution of 9.93 g (30.9 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one (Example 121, Step F) in DMF (65 mL) was added 2.47 g (60 wt. % in mineral oil, 61.8 mmol) of sodium hydride. The resulting yellow slurry was stirred at 0° C. for 5 min, then was warmed to room temperature and stirred for an additional 12 min. The reaction was re-cooled to 0° C. and 11.4 mL (77 mmol) of ethyl 2-bromobutyrate was added slowly via syringe over 10 min. The resulting orange slurry was warmed to room temperature and stirred for 4.75 h, and then was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×), and the combined organic layers were washed with water (2×) and sat. aq. NaCl solution (1×). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (38 to 40% EtOAc/hexanes, gradient elution) provided the title compound as a light yellow solid.

1. temperaturewas warmed to room temperature
2. stirringstirred for an additional 12 min
3. temperatureThe reaction was re-cooled to 0° C.
4. temperatureThe resulting orange slurry was warmed to room temperature
5. stirringstirred for 4.75 h
6. customwas quenched with saturated aqueous ammonium chloride
7. extractionThe mixture was extracted with ethyl acetate (3×)
8. washthe combined organic layers were washed with water (2×) and sat. aq. NaCl solution (1×)
9. dry with materialThe organic layer was dried over Na2SO4
10. filtrationfiltered
11. concentrationthe filtrate was concentrated
12. customPurification of the residue by flash chromatography on silica gel (38 to 40% EtOAc/hexanes, gradient elution)

ORD record

ord-742aefad6ddd48609f3bc6df43a69432

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296736B2