Sodium hydride → (6S)-6-(3,5-dimethylphenyl)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazinan-2-one

HRID 537991Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 537991
[H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C@H:11]2[O:16][C:15](=[O:17])[NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([CH3:10])[CH:9]=1.Br[CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=1[O:40][CH3:41]>C1COCC1>[CH3:3][C:4]1[CH:5]=[C:6]([C@H:11]2[O:16][C:15](=[O:17])[N:14]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[CH:32][C:31]=3[O:40][CH3:41])[CH2:13][CH2:12]2)[CH:7]=[C:8]([CH3:10])[CH:9]=1

Komponenten

5

Edukt 3

HCID 24758Sodium hydrideHCID 533638292'-(Bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl2×HCID 57544374(6S)-6-(3,5-dimethylphenyl)-1,3-oxazinan-2-one2×

Produkt 1

HCID 24739600(6S)-6-(3,5-dimethylphenyl)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazinan-2-one

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel3×

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

To a stirred suspension of sodium hydride (60% in oil; 7.4 mg; 0.185 mmol) in THF (1.5 mL) at 0° C. under N2 was added a solution of (6S)-6-(3,5-dimethylphenyl)-1,3-oxazinan-2-one (Intermediate 21; 30 mg; 0.148 mmol) in THF (2 mL) dropwise. The reaction was stirred at 0° C. for 20 min prior to addition of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 13; 50 mg; 0.123 mmol) as a solution in THF (1.5 mL). The reaction was allowed to warm to room temperature and stirred for 72 h, then quenched with H2O and partitioned between EtOAc (25 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified first by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) and then by chiral HPLC (Chiralpak AD column; 15% IPA/heptane) to afford (6S)-6-(3,5-dimethylphenyl)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazinan-2-one as a clear oil. LCMS=530.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.66 (d, J=7.8 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 7.01-6.96 (m, 4H), 6.70 (d, J=12.1 Hz, 1H), 5.23-5.13 (m, 1H), 4.66-4.49 (m, 2H), 3.78 (s, 3H), 3.26-3.20 (m, 1H), 3.17-3.06 (m, 1H), 3.01-2.93 (m, 1H), 2.34 (s, 6H), 2.18-2.13 (m, 1H), 2.09-2.02 (m, 1H), 1.29-1.24 (m, 6H).

Aufarbeitung

  1. temperatureto warm to room temperature
  2. stirringstirred for 72 h
  3. customquenched with H2O
  4. custompartitioned between EtOAc (25 mL) and H2O (10 mL)
  5. extractionThe aqueous layer was extracted with EtOAc (3×25 mL)
  6. washThe combined organic layers were washed with brine (25 mL)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified first by flash silica gel chromatography (0-25% EtOAc/hexanes gradient)

Quellen und Nachweise

ORD-Eintrag
ord-cc88f6b80629407d90a9b2c58f1096f8
Quelldatensatz
uspto-grants-2014_10
Patentnummer
US08865707B2

Notizen zur Reaktion

Wird geladen…