Sodium hydride → Benzyl 4-((1R,2S)-2-{2-[(3-methyl-5-nitropyridin-2-yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate

Temperature

45 °C

To the solution of benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (Intermediate 10, 1.84 g, 6.06 mmol) in 15 ml of DMSO was added NaH and the resulting solution was stirred at 45° C. for 15 min. The mixture was then cooled to 0° C. via an ice/water bath and 2-chloro-3-methyl-5-nitropyridine (1.05 g, 6.06 mmol) was added in portions. The reaction mixture turned dark and became a slurry. After 10 minutes, the ice/water bath was removed and 20 ml of DMSO was added. The resulting mixture was stirred for 40 minutes allowing to warm to room temperature. The reaction was quenched by water and extracted with ethyl acetate (3×100 mL). The organics were combined and washed with brine, dried on sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified via Biotage column (65M silica gel) using ethyl acetate in hexane (0-60%, 1000 ml) to afford the title compound. MS (ESI) m/z 440 [M+H]+.

1. temperatureThe mixture was then cooled to 0° C. via an ice/water bath
2. waitAfter 10 minutes
3. customthe ice/water bath was removed
4. addition20 ml of DMSO was added
5. stirringThe resulting mixture was stirred for 40 minutes
6. temperatureto warm to room temperature
7. customThe reaction was quenched by water
8. extractionextracted with ethyl acetate (3×100 mL)
9. washwashed with brine
10. customdried on sodium sulfate
11. filtrationfiltered
12. concentrationthe filtrate concentrated under reduced pressure
13. customThe residue was purified via Biotage column (65M silica gel)

ORD record

ord-4088862e50b843d1aac542c78d2caf5c

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08957062B2