Triethylamine → Ethyl(1R,2R,3S,6S)-3-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-(4-fluorophenyl)-6-(hydroxymethyl)cyclohexanecarboxylate

Temperatur

0 °C

To a solution of intermediate carboxylic acid (2.7 g, 4.91 mmol) from Step A in 60 mL THF was added isobutyl chloroformate (0.96 mL, 7.32 mmol) and triethyl amine (1.23 mL, 8.84 mmol). The mixture was stirred at 0° C. for 0.5 hr then at room temperature for 0.5 hr. The white precipitate was filtered and the solid was washed with dry THF. The filtrate was added to a suspension of 1 g NaBH4 in 3 mL water at 0° C. The resulting mixture was stirred at room temperature for 16 hr, quenched with 2 N aq. HCl (20 mL), then diluted with ethyl acetate (50 mL). The organic layer was separated and the aqueous was extracted with ethyl acetate (2×60 mL). The combined organic extract was washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was purified by column chromatography (2:1 hexane:ethyl acetate) to give the title compound (1.8 g). 1H-NMR (CDCl3) δ: 7.71 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, m), 4.45 (1H, q, J=6.4 Hz), 3.83 (2H, m), 3.55 (2H, m), 3.35 (1H, m), 2.93 (1H, t, J=11.0 Hz), 2.47 (1H, t, J=11.0Hz), 2.37 (1H, s), 2.33 (1H, m), 1.97 (2H, m), 1.62-1.50 (2H, m), 1.20 (1H, m), 1.33 (3H, d, J=6.4 Hz), 0.90 (3H, t, J=7.1 Hz).

1. waitat room temperature for 0.5 hr
2. filtrationThe white precipitate was filtered
3. washthe solid was washed with dry THF
4. additionThe filtrate was added to a suspension of 1 g NaBH4 in 3 mL water at 0° C
5. stirringThe resulting mixture was stirred at room temperature for 16 hr
6. customquenched with 2 N aq. HCl (20 mL)
7. additiondiluted with ethyl acetate (50 mL)
8. customThe organic layer was separated
9. extractionthe aqueous was extracted with ethyl acetate (2×60 mL)
10. extractionThe combined organic extract
11. washwas washed with brine
12. dry with materialdried over MgSO4
13. filtrationfiltered
14. customthe solvent was removed under vacuum
15. customThe residue was purified by column chromatography (2:1 hexane:ethyl acetate)

ORD-Eintrag

ord-ce30817de4bd43b4804db87b1a5fa9b8

Quelldatensatz

uspto-grants-2010_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07683068B2