Allyl bromide → (R)-2-(3-chloropropyl)-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpent-4-enamide

Temperature

-78 °C

To a magnetically stirred suspension of LiCl (83 g, 1.96 mol) in THF (700 mL) at room temperature was added diisopropylamine (104 mL, 736 mmol) in one portion. nBuLi (2.5M in hexane, 281 mL, 703 mmol) was added dropwise over 30 min using an addition funnel. The light yellow mixture stirred at −78° C. for 20 min and then was warmed to 0° C. for 15 min. The mixture was then cooled to −78° C. and 5-chloro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpentanamide (92.8 g, 327 mmol) in THF (330 mL) was added dropwise over 30 min using an addition funnel. The mixture was stirred at −78° C. for 1 h and then was warmed to 0° C. for 25 min. Allylbromide (41.5 mL, 490 mmol) was then added slowly over 2 min via syringe and then the reaction was warmed to room temperature. The reaction stirred at room temperature for 50 min and was judged complete by LC/MS. The mixture was cooled to 0° C. and saturated aqueous NaHCO3 (400 mL) and H2O (200 mL) were added. EtOAc was added, the phases were separated and the aqueous phase was extracted with EtOAc (1500 mL total). The combined with organic layers were washed with 1N HCl (4×150 mL), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to furnish (R)-2-(3-chloropropyl)-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpent-4-enamide as an orange oil (101.2 g, 312 mmol, 95%). The crude material was carried on without further purification. LC/MS (m/z=306.0).

1. temperaturewas warmed to 0° C. for 15 min
2. temperatureThe mixture was then cooled to −78° C.
3. stirringThe mixture was stirred at −78° C. for 1 h
4. temperaturewas warmed to 0° C. for 25 min
5. temperaturethe reaction was warmed to room temperature
6. stirringThe reaction stirred at room temperature for 50 min
7. temperatureThe mixture was cooled to 0° C.
8. customthe phases were separated
9. extractionthe aqueous phase was extracted with EtOAc (1500 mL total)
10. washwere washed with 1N HCl (4×150 mL), brine
11. dry with materialdried over MgSO4
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure

ORD record

ord-7a89b1e073bf49808ba5bf58992198e3

Source dataset

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08198453B2