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Ethyl bromodifluoroacetate → (R)-ethyl 3-((R)-1,1-dimethylethylsulfinamido)-2,2-difluoro-3-(2-fluorophenyl)butanoate

HRID 530279
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 530279
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9].Br[C:18]([F:25])([F:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C([Zn]CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:16][C:13]([CH3:14])([S@:11]([NH:10][C@@:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:9])[C:18]([F:25])([F:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])[CH3:15]
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

6

Edukt 3

HCID 69585Ethyl bromodifluoroacetateHCID 118307974(R)-N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamideHCID 178418750HCID 178418750, Verbindung

Produkt 1

HCID 67467047(R)-ethyl 3-((R)-1,1-dimethylethylsulfinamido)-2,2-difluoro-3-(2-fluorophenyl)butanoateAusbeute 59,7 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 84599
Chlorotris(triphenylphosphine)rhodium(I)
Katalysator
HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

Tris(triphenylphosphine)rhodium(I) chloride (1.50 g, 1.62 mmol) was placed in a dry round bottom flask. The flask was evacuated and filled with argon (×3). (R)—N-(1-(2-Fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (15.6 g, 64.6 mmol) was dissolved in tetrahydrofuran (265 ml) (dried over 4 Å MS) and added to the reaction flask followed by ethyl bromodifluoroacetate (26.2 g, 16.6 ml, 129 mmol). The dark red/orange reaction mixture was cooled to 0° C. using an ice/water bath. Diethyl zinc (126 ml, 126 mmol, 1 M in hexane) was added in a dropwise manner. Upon complete addition the reaction was stirred at 0° C. for an additional 1 h, the cooling was removed and the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (250 mL) and quenched with saturated aqueous NaHCO3 (100 mL). The resulting suspension was filtered through a plug of celite, the phases were separated, and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified using a CombiFlash system (330 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→60:40) to afford (R)-ethyl 3-((R)-1,1-dimethylethylsulfinamido)-2,2-difluoro-3-(2-fluorophenyl)butanoate (14.1 g, 59.7% yield). The stereochemistry was assigned based on literature precedence (WO2012110459) 1H NMR (600 MHz, CDCl3) δ 7.46 (t, J=8.0 Hz, 1H), 7.41-7.35 (m, 1H), 7.19-7.14 (m, 1H), 7.07 (dd, J=13.0, 8.2 Hz, 1H), 4.65 (d, J=2.6 Hz, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.07 (s, 3H), 1.30-1.21 (m, 12H).

Aufarbeitung

  1. customThe flask was evacuated
  2. additionfilled with argon (×3)
  3. additionadded to the reaction flask
  4. additionUpon complete addition the reaction
  5. customthe cooling was removed
  6. stirringthe reaction was stirred at room temperature overnight
  7. additionThe reaction was diluted with ethyl acetate (250 mL)
  8. customquenched with saturated aqueous NaHCO3 (100 mL)
  9. filtrationThe resulting suspension was filtered through a plug of celite
  10. customthe phases were separated
  11. dry with materialthe organic layer was dried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure
  14. customThe crude material was purified
  15. washa CombiFlash system (330 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→60:40)

Quellen und Nachweise

ORD-Eintrag
ord-a8b820b11e9b42e69906aa82c9961f2b
Quelldatensatz
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09353084B2

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