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

HRID 880547노트

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HRID 880547 반응식
[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

참가 물질

4

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

생성물 1

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

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온도
65 °C

실험 절차

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); C21H15F12NO (MW, 525.33), LCMS (EI) m/e 526.0 (M++H).

후처리

  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

출처 및 근거

ORD 기록
ord-585e7343b8f04a4d890aa7f476386cda
출처 데이터셋
uspto-grants-2015_03
특허 번호
US08993582B2

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