Ammonium Chloride → 1-Benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol

HRID 1931875

Reaktionsgleichung

Reaktionsgleichung von HRID 1931875
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=2[F:9])([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1

Komponenten

6

Edukt 4

HCID 25517Ammonium ChlorideHCID 698901-Benzyl-3-pyrrolidinoneHCID 27332601-Bromo-2,3-difluorobenzeneHCID 178418339Butyllithium

Produkt 1

HCID 685158491-Benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 3283Diethyl EtherLösungsmittel2×

Reaktionsbedingungen

Temperatur
-78 °C

Versuchsvorschrift

To a solution of 1-bromo-2,3-difluorobenzene (5.79 g, 30 mmol) in dry diethyl ether (50 mL) under nitrogen at −78° C., was added dropwise n-butyllithium (2.5 M in hexane, 13.2 mL, 33 mmol). The mixture was stirred for 30 min at −78° C. after which a solution of 1-benzylpyrrolidin-3-one (5.25 g, 30 mmol) in dry diethyl ether (15 mL) was added drop wise. The mixture was stirred at −78° C. for 1 h and at ambient temperature for 1 h. Saturated aqueous ammonium chloride (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (ethylacetate/isooctane/triethylamine, 10:85:5). Yield: 3.7 g. The enantiomers were separated by HPLC on Kromasil 5-Cellucoat (heptane/2-propanol/diethyl amine, 99:1:0.1): (+)-enantiomer (1.69 g). [α]D=+47.0° (methanol). MS m/z (rel. intensity, 70 eV) 289 (M+, 38), 198 (76), 133 (64), 132 (47), 91 (bp). (−)-enantiomer (1.54 g). [α]D=−46.2° (methanol). MS m/z (rel. intensity, 70 eV) 289 (M+, 11), 198 (43), 133 (56), 132 (40), 91 (bp).

Aufarbeitung

  1. additionwas added drop wise
  2. extractionthe mixture was extracted with ethyl acetate (2×50 mL)
  3. dry with materialThe combined organic phase was dried (Na2SO4)
  4. filtrationfiltered
  5. customevaporated
  6. customPurification by flash chromatography on silica gel (ethylacetate/isooctane/triethylamine, 10:85:5)
  7. customThe enantiomers were separated by HPLC on Kromasil 5-Cellucoat (heptane/2-propanol/diethyl amine, 99:1:0.1)

Quellen und Nachweise

ORD-Eintrag
ord-715cecb4969c46b6851f5a63a9dd32cf
Quelldatensatz
uspto-grants-2012_05
Patentnummer
US08188301B2

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