1-Methyl-4-piperidone → 1-methyl-4-(2-trityl-2,3-dihydro-1H-isoindol-5-yl)-piperidin-4-ol

HRID 334969

Reaktionsgleichung

Reaktionsgleichung von HRID 334969
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5]2.C([Li])CCC.[CH3:35][N:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1>C1COCC1>[CH3:35][N:36]1[CH2:41][CH2:40][C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][N:6]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]3)([OH:42])[CH2:38][CH2:37]1

Komponenten

5

Edukt 3

HCID 740491-Methyl-4-piperidoneHCID 592631135-Bromo-2-trityl-isoindolineHCID 178418339Butyllithium

Produkt 1

HCID 592631371-methyl-4-(2-trityl-2,3-dihydro-1H-isoindol-5-yl)-piperidin-4-olAusbeute 57 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

Under nitrogen, a solution of 5-bromo-2-trityl-2,3-dihydro-1H-isoindole (2.03 g, 4.6 mmol) in THF (20 mL) was cooled to −78° C. n-Butyllithium solution (2.5M in hexanes, 2.0 mL, 5 mmol) was added over 5 minutes, then after 10 minutes, 1-methyl-4-piperidone was added dropwise. After a further hour, the cooling bath was removed and the reaction quenched with sodium bicarbonate solution. The mixture was extracted with ethyl acetate then the organic phase was washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica (gradient elution with 2M methanolic ammonia/dichloromethane, 0% to 5%) to afford 1-methyl-4-(2-trityl-2,3-dihydro-1H-isoindol-5-yl)-piperidin-4-ol as a pink foam (1.25 g, 57%). 1H NMR (MeOH-d4) 7.56 (6H, dd), 7.28 (6H, t), 7.25-7.21 (2H, m), 7.15 (3H, t), 7.03 (1H, d), 3.92 (2H, s), 3.91 (2H, s), 2.70 (2H, d), 2.53 (2H, td), 2.33 (3H, s), 2.06 (2H, td), 1.70 (2H, d). MS: [M+H]+ 475.

Aufarbeitung

  1. additionwas added over 5 minutes
  2. waitAfter a further hour
  3. customthe cooling bath was removed
  4. customthe reaction quenched with sodium bicarbonate solution
  5. extractionThe mixture was extracted with ethyl acetate
  6. washthe organic phase was washed with brine
  7. dry with materialdried (MgSO4)
  8. concentrationconcentrated
  9. customThe residue was purified by flash chromatography on silica (gradient elution with 2M methanolic ammonia/dichloromethane, 0% to 5%)

Quellen und Nachweise

ORD-Eintrag
ord-ca6cf0e626724cc5962b1974b5f8801e
Quelldatensatz
uspto-grants-2014_11
Patentnummer
US08883790B2

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