Triethylamine → 3-{2(s)-Biphenyl-4-yl-3-cyclopentyl-propionyl}-4(s)-isopropyl-oxazolidin-2-one

Temperatur

-78 °C

A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (prepared in Example 1A, 1.12 g, 3.80 mmol) in dry tetrahydrofuran (36 mL) under nitrogen was cooled to −78° C. and then treated with triethylamine (606 mL, 4.35 mmol). The reaction mixture was stirred at −78° C. for 15 min and then treated dropwise with trimethylacetyl chloride (491 mL, 3.98 mmol). The resulting reaction mixture was stirred at −78° C. for 15 min, at which time, the cooling bath was removed, and the reaction mixture was allowed to warm to 25° C. where it was stirred for 45 min. At this time, the reaction mixture was cooled back to −78° C. for the addition of the chiral auxiliary. Into a separate reaction flask, a solution of (4S)-(−)-4-isopropyl-2-oxazolidinone (467.9 mg, 3.62 mmol) in dry tetrahydrofuran (18 mL) under nitrogen was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (1.6 mL, 3.80 mmol). After complete addition of the n-butyllithium, the reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. This cloudy white solution was then added dropwise by syringe to the previously cooled (−78° C.) pivalate solution. The resulting reaction mixture was stirred at −78° C. for 1 h and then allowed to gradually warm to 25° C. The reaction mixture was stirred at 25° C. for 15 h. The resulting reaction mixture was quenched with a saturated aqueous sodium bisulfite solution and concentrated in vacuo to remove tetrahydrofuran. The resulting aqueous residue was diluted with ethyl acetate (150 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 19/1 to 17/3 hexanes/ethyl acetate gradient elution) afforded the higher Rf product 3-{2(S)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopropyl-oxazolidin-2-one (679.2 mg, 92%) as a yellow oil: EI-HRMS m/e calcd for C26H31NO3 (M+) 405.2304, found 405.2310; and the lower Rf product 3-{2(R)-biphenyl-4-yl-3-cyclopentyl-propionyl}-4(S)-isopropyl-oxazolidin-2-one (127.4 mg, 17%) as a yellow oil: EI-HRMS m/e calcd for C26H31NO3 (M+) 405.2304, found 405.2313.

1. customThe resulting reaction mixture
2. stirringwas stirred at −78° C. for 15 min, at which time
3. customthe cooling bath was removed
4. temperatureto warm to 25° C. where it
5. stirringwas stirred for 45 min
6. temperatureAt this time, the reaction mixture was cooled back to −78° C. for the addition of the chiral auxiliary
7. customInto a separate reaction flask
8. temperatureto warm to 25° C. where it
9. stirringwas stirred for 1 h
10. additionThis cloudy white solution was then added dropwise by syringe to the
11. customThe resulting reaction mixture
12. stirringwas stirred at −78° C. for 1 h
13. temperatureto gradually warm to 25° C
14. stirringThe reaction mixture was stirred at 25° C. for 15 h
15. customThe resulting reaction mixture
16. customwas quenched with a saturated aqueous sodium bisulfite solution
17. concentrationconcentrated in vacuo
18. customto remove tetrahydrofuran
19. additionThe resulting aqueous residue was diluted with ethyl acetate (150 mL)
20. washThe organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL)
21. dry with materialdried over sodium sulfate
22. filtrationfiltered
23. concentrationconcentrated in vacuo
24. washFlash chromatography (Merck Silica gel 60, 230-400 mesh, 19/1 to 17/3 hexanes/ethyl acetate gradient elution)

ORD-Eintrag

ord-3b1ff11e93964c8a9161108caba0ade6

Quelldatensatz

uspto-grants-2002_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06384220B2