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

HRID 2245247Notes

Reaction equation

HRID 2245247 reaction equation
[F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22](O)=[O:23])[C@@H:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:17]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C>C1COCC1>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:17]2[C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 86628111HCID 86628111, compound

Product 1

HCID 86628112Ethyl(1R,2R,3S,6S)-3-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-(4-fluorophenyl)-6-(hydroxymethyl)cyclohexanecarboxylateYield 68.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-ce30817de4bd43b4804db87b1a5fa9b8
Source dataset
uspto-grants-2010_03
Patent number
US07683068B2

Reaction notes

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