Citric Acid → 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-phenylmethyldihydrofuran-2-(3H)one

HRID 263758Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 263758
[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CN1CCCN(C)C1=O.C(OCC)(=O)C.O>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]

Komponenten

10

Edukt 5

HCID 311Citric AcidHCID 1032Propionic AcidHCID 7498Benzyl BromideHCID 2733832Lithium HexamethyldisilazideHCID 10870461tert-butyl(1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate

Produkt 1

HCID 117320045(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-phenylmethyldihydrofuran-2-(3H)one

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittel2×HCID 8857Ethyl AcetateLösungsmittelHCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Lösungsmittel

Reaktionsbedingungen

Temperatur
-75 °C

Versuchsvorschrift

(A. K. Ghosh, S. P. McKee, and W. J. Thompson, J. Org. Chem. 56, 6500 (1991)). Under a nitrogen atmosphere, a solution of 1943 g (6.32 mol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one in 12.0 l of THF and 1.9 l of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is cooled to -75° C., at an internal temperature of below -70° C. 14000 ml of lithium bis(trimethylsilyl)amide (IM) in THF (Aldrich) are added, and the mixture is then stirred for 20 min at -75° C. Over a period of 1 h, 835 ml (7.00 mol) of benzyl bromide are added thereto, the internal temperature not being allowed to exceed -70° C., and the mixture is stirred for 30 min at -75° C. to complete the reaction. There are then added to the clear solution at from -75 to -70° C. 2320 ml of propionic acid (90 min) followed by 2320 ml of water (1 h), the temperature being allowed to rise to -10° C. The reaction mixture is poured onto 30 l of ethyl acetate and 35 l of 10% citric acid solution, and the aqueous phase is removed and re-extracted twice with 10 l of ethyl acetate each time. The organic phases are washed three times with 12 l of sat. sodium bicarbonate solution each time, with 20 l of brine and twice with 20 l of water each time, and concentrated, and the oily residue is taken up in 10 l of toluene and concentrated by evaporation to a residual volume of approximately 5 1. Filtration of the evaporation residue through 4 kg of Merck silica gel (0.063-0.200 mm), subsequent washing with toluene and crystallisation of the crude product from hexane (4 l of hexane/kg of crude product) yields the title compound: TLC Rf (D)=0.54; FAB-MS (M+H)+ =414.

Aufarbeitung

  1. waitOver a period of 1 h
  2. customto exceed -70° C.
  3. stirringthe mixture is stirred for 30 min at -75° C.
  4. customthe reaction
  5. additionThere are then added to the clear solution at from -75 to -70° C
  6. customto rise to -10° C
  7. customthe aqueous phase is removed
  8. extractionre-extracted twice with 10 l of ethyl acetate each time
  9. washThe organic phases are washed three times with 12 l of sat. sodium bicarbonate solution each time
  10. concentrationwith 20 l of brine and twice with 20 l of water each time, and concentrated
  11. concentrationconcentrated by evaporation to a residual volume of approximately 5 1
  12. filtrationFiltration of the evaporation residue through 4 kg of Merck silica gel (0.063-0.200 mm)
  13. washsubsequent washing with toluene and crystallisation of the crude product from hexane (4 l of hexane/kg of crude product)

Quellen und Nachweise

ORD-Eintrag
ord-4f66a03130084c01b96ee0f6ca596353
Quelldatensatz
uspto-grants-1997_07
Patentnummer
US05643878

Notizen zur Reaktion

Wird geladen…