Ammonium Chloride → Benzyl 1-benzyl-3-(2-(tert-butoxy)-2-oxoethyl)-4-methylpyrrolidine-3-carboxylate

Temperatur

-70 °C

Benzyl (3RS,4SR)-1-benzyl-4-methylpyrrolidine-3-carboxylate obtained in Example 1f (30 g, 97.4 mmol) was dissolved in tetrahydrofuran (300 ml), which was cooled to −70° C. with stirring under nitrogen. A 1.11M lithium diisopropylamide/n-hexane-tetrahydrofuran solution (105 ml, 116 mmol) was added dropwise over 20 minutes so that the internal temperature did not exceed −64.3° C. The mixture was stirred at −70° C. for 1 hour, and tetrahydrofuran (30 ml) and tert-butyl bromoacetate (26.6 g, 136 mmol) were then added dropwise over 10 minutes so that the internal temperature did not exceed −60° C. The reaction mixture was stirred at −70° C. for further one hour, and a saturated aqueous ammonium chloride solution was then added to the reaction mixture. Immediately thereafter, the reaction mixture was diluted with water and ethyl acetate was added. The organic layer was washed with brine and a 5 N aqueous hydrochloric acid solution, and then dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane). The residue was further purified by NH silica gel column chromatography (elution solvent: heptane/ethyl acetate=98/2) to give the title compound (6 g, yield: 14.5%).

1. customdid not exceed −64.3° C
2. stirringThe mixture was stirred at −70° C. for 1 hour
3. customdid not exceed −60° C
4. stirringThe reaction mixture was stirred at −70° C. for further one hour
5. additionwas added
6. washThe organic layer was washed with brine
7. dry with materiala 5 N aqueous hydrochloric acid solution, and then dried over magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated
10. customThe residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane)
11. customThe residue was further purified by NH silica gel column chromatography (elution solvent: heptane/ethyl acetate=98/2)

ORD-Eintrag

ord-6eb98e50d9ae47718c371eb41a903878

Quelldatensatz

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08476301B2