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 537991ノート

反応式

HRID 537991 の反応式
[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

参加物

5

反応物 3

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

生成物 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

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒3 回

反応条件

温度
0 °C

実験手順

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).

後処理

  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)

出典と根拠

ORDレコード
ord-cc88f6b80629407d90a9b2c58f1096f8
出典データセット
uspto-grants-2014_10
特許番号
US08865707B2

反応ノート

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