Sodium Carbonate → Anacetrapib

HRID 1028535

반응식

HRID 1028535 반응식
[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

참가 물질

6

반응물 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

생성물 1

HCID 11556427Anacetrapib

시약·촉매·용매 2

HCID 178418397HCID 178418397, 화합물촉매HCID 66847609Benzene ethanol water용매

반응 조건

온도
100 °C

실험 절차

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, 0.5 H), 7.57 (s, 1 H), 7.33 (d, J=8 Hz, 1 H), 7.27 (d, J=9.9 Hz, 2 H), 7.02-6.98 (m, 1 H), 6.89 (d, J=8.5 Hz, 0.5 H), 6.82 (d, J=8.5 Hz, 0.5 H), 6.45 (d, J=12.1 Hz, 0.5 H), 6.35 (d, J=11.9 Hz, 0.5 H), 4.94 (d, J=16.0 Hz, 0.5 H), 4.87 (d, J=15.8 Hz, 0.5 H), 4.54 (d, J=8.0 Hz, 0.5 H), 4.50 (d, J=7.8 Hz, 0.5 H), 3.74-3.66 (m, 1 H), 3.23-3.15 (m, 1 H), 3.12 (s, 1.5 H), 2.99 (s, 1.5 H), 2.97-2.92 (m, 0.5H), 2.89-2.84 (m, 0.5 H), 1.21-1.09 (m, 6 H), −0.27 (d, J=6.7 Hz, 1.5 H), −0.40 (d, J=6.7 Hz, 1.5 H).

후처리

  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)

출처 및 근거

ORD 기록
ord-a398b0b1b59d416ea1a8bb029f87af7c
출처 데이터셋
uspto-grants-2014_05
특허 번호
US08735435B2

연결된 노트

불러오는 중…