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

HRID 334209ノート

反応式

HRID 334209 の反応式
[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

参加物

4

反応物 3

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

生成物 1

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

反応条件

温度
65 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-9287865a823e4c05afe2da882d67cffb
出典データセット
uspto-grants-2014_11
特許番号
US08883806B2

反応ノート

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