Methanol → (2R)-alpha,alpha-Bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol

HRID 334209Notes

Reaction equation

HRID 334209 reaction equation
[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]2([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[O:17]C(=O)[N:15]3[CH2:19][CH2:20][CH2:21][C@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[OH-].[K+]>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)([C@H:14]2[CH2:21][CH2:20][CH2:19][NH:15]2)[OH:17])[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:8]=1

Participants

4

Reactant 3

HCID 887MethanolHCID 14797Potassium HydroxideHCID 71650775(7aR)-1,1-bis(3,5-bis(trifluoromethyl)phenyl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one

Product 1

HCID 71310462(2R)-alpha,alpha-Bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanolYield 79%

Conditions

Temperature
65 °C

Procedure

To a stirred solution of crude (7aR)-1,1-bis(3,5-bis(trifluoromethyl)phenyl)tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one ((R)-32, 11.03 g, 20.0 mmol) in methanol (MeOH, 80 mL, 1975 mmol) was added solid potassium hydroxide (KOH, 3.366 g, 60.0 mmol, 3.0 equiv) at room temperature. The resulting dark reaction mixture was heated to 65° C. and stirred at 65° C. for 22 h. When LCMS showed the reaction was deemed complete, the reaction mixture was cooled to room temperature before the solvent was evaporated under reduced pressure. The residue was then treated with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was then purified by Combiflash (SiO2) with 0-30% EtOAc/hexane gradient elution to afford (2R)-bis(3,5-bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol ((R)-33, 8.30 g, 10.51 g theoretical, 79% yield for 2 steps) as a yellow viscous paste. For (R)-33: 1H NMR (CD3OD, 400 MHz) δ ppm 8.24 (s, 2H), 8.16 (s, 2H), 7.85 (s, 2H), 4.49 (t, 1H, J=7.7 Hz), 2.92 (m, 2H), 1.74 (m, 2H), 1.67 (m, 1H), 1.55 (m, 1H); C21H15F12N0 (MW, 525.33), LCMS (EI) m/e 526.0 (M++H).

Workup

  1. customThe resulting dark reaction mixture
  2. temperaturethe reaction mixture was cooled to room temperature before the solvent
  3. customwas evaporated under reduced pressure
  4. additionThe residue was then treated with water (100 mL)
  5. extractionextracted with EtOAc (2×100 mL)
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over magnesium sulfate (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was then purified by Combiflash (SiO2) with 0-30% EtOAc/hexane gradient elution

Sources & evidence

ORD record
ord-9287865a823e4c05afe2da882d67cffb
Source dataset
uspto-grants-2014_11
Patent number
US08883806B2

Reaction notes

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