Ammonium Chloride → (4S)-4-(1-Methylethyl)-3-(5,5,5-trifluoro-1-oxopentyl)-2-oxazolidinone

Temperature

0 °C

To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at −78° C. was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride, dissolved in THF (20 mL), was added via cannula over 15 min. The reaction mixture was warmed to 0° C., and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, and the mixture was extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP® SiO2 120 g). Concentration of the appropriate fractions provided Intermediate S-1H (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 4.44 (1H, dt, J=8.31, 3.53 Hz), 4.30 (1H, t, J=8.69 Hz), 4.23 (1H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2H, m), 2.32-2.44 (1H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2H, m), 1.88-2.00 (2H, m), 0.93 (3H, d, J=7.05 Hz), 0.88 (3H, d, J=6.80 Hz).

1. concentrationThe reaction mixture was concentrated under reduced pressure
2. customto give pale yellow oil
3. stirringAfter stirring for 10 min
4. additionwas added via cannula over 15 min
5. temperatureto warm to room temperature as the bath
6. temperaturewarmed
7. stirringstirred overnight
8. extractionthe mixture was extracted with EtOAc (2×)
9. washThe combined organics were washed with brine
10. dry with materialdried (Na2SO4)
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure
13. customThe crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP® SiO2 120 g)
14. customConcentration of the appropriate fractions provided Intermediate S-1H (7.39 g, 86%) as a colorless oil

ORD record

ord-3b19280538374cebb344f897707c44e2

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09273014B2