Sodium Carbonate → Anacetrapib

HRID 1994505

反応式

HRID 1994505 の反応式
[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:38](B(O)O)=[C:37]([O:47][CH3:48])[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:38]3[CH:39]=[C:40]([CH:41]([CH3:43])[CH3:42])[C:35]([F:34])=[CH:36][C:37]=3[O:47][CH3:48])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

参加物

6

反応物 3

HCID 10340Sodium CarbonateHCID 53363739(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acidHCID 53363742(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

生成物 1

HCID 11556427Anacetrapib

試薬・触媒・溶媒 2

HCID 178418397HCID 178418397、化合物触媒HCID 66847609Benzene ethanol water溶媒

反応条件

温度
100 °C

実験手順

A stirred mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]4-methyl-1,3-oxazolidin-2-one (4.29 g; 7.19 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78) (4.57 g; 21.57 mmol), tetrakis(triphenylphosphine)palladium (0) (1.0 g; 0.86 mmol), and sodium carbonate (6.35 g) in C6H6/EtOH/H2O (120 mL/17 mL/51 mL) was heated at reflux (100° C.) under N2 for 14 h. The reaction was partitioned between EtOAc (200 mL) and H2O (100 mL). The aqueous phase was extracted with EtOAc (3×200 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica-gel flash chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}4-methyl-1,3-oxazolidin-2-one as a yellow solid. To remove the yellow impurity, 2.7 g were dissolved in 165 mL EtOH and 275 mg decolorizing charcoal was added (activated carbon, Darco, G-60, 100 mesh powder, Aldrich). The mixture was stirred at room temperature for 40 min, filtered, and concentrated in vacuo. Trituration with ca. 25 mL hexanes afforded 2.46 g of the title compound as a white solid. 1H NMR indicated trace impurities which were removed by silica gel flash chromatography (0-15% EtOAc/hexanes gradient). Residual solvent was removed by lyophilization from acetonitrile. LCMS=638.3 (M+1)+. 1H NMR (benzene-d6, 500 MHz, 1:1 mixture of atropisomers): δ 7.82 (s, 0.5H), 7.60 (s, 0.5H), 7.57 (s, 1H), 7.33 (d, J=8 Hz, 1H), 7.27 (d, J=9.9 Hz, 2H), 7.02-6.98 (m, 1H), 6.89 (d, J=8.5 Hz, 0.5H), 6.82 (d, J=8.5 Hz, 0.5H), 6.45 (d, J=12.1 Hz, 0.5H), 6.35 (d, J=11.9 Hz, 0.5H), 4.94 (d, J=16.0 Hz, 0.5H), 4.87 (d, J=15.8 Hz, 0.5H), 4.54 (d, J=8.0 Hz, 0.5H), 4.50 (d, J=7.8 Hz, 0.5H), 3.74-3.66 (m, 1H), 3.23-3.15 (m, 1H), 3.12 (s, 1.5H), 2.99 (s, 1.5H), 2.97-2.92 (m, 0.5H), 2.89-2.84 (m, 0.5H), 1.21-1.09 (m, 6H), −0.27 (d, J=6.7 Hz, 1.5H), −0.40 (d, J=6.7 Hz, 1.5H).

後処理

  1. temperaturewas heated
  2. customThe reaction was partitioned between EtOAc (200 mL) and H2O (100 mL)
  3. extractionThe aqueous phase was extracted with EtOAc (3×200 mL)
  4. washThe combined organic phases were washed with brine (100 mL)
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by silica-gel flash chromatography (0-25% EtOAc/hexanes gradient)

出典と根拠

ORDレコード
ord-0c2cca9358b84e67a9cce73bb2f1cdc3
出典データセット
uspto-grants-2010_01
特許番号
US07652049B2

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