Cesium carbonate → Tert-butyl 5-chloro-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate

HRID 1849606ノート

反応式

HRID 1849606 の反応式
[F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([CH2:8][C:9](OCC)=[O:10])[CH2:4][CH2:3]1.[BH4-].[Li+].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.CO.CS(C)=O.O>[Cl:17][C:18]1[C:19]([O:10][CH2:9][CH2:8][CH:5]2[CH2:6][CH2:7][C:2]([F:1])([F:14])[CH2:3][CH2:4]2)=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]

参加物

9

反応物 4

HCID 10796Cesium carbonateHCID 4148881Lithium borohydrideHCID 58042499Tert-butyl 5-chloro-2,4-difluorobenzoateHCID 59304597HCID 59304597、化合物

生成物 1

HCID 86703462Tert-butyl 5-chloro-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate収率 29%

試薬・触媒・溶媒 4

HCID 679Dimethyl Sulfoxide溶媒HCID 887Methanol溶媒HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
0 °C

実験手順

To a of solution ethyl 2-(4,4-difluorocyclohexyl)acetate (1.44 g, 7.00 mmol) in anhydrous tetrahydrofuran (23 mL) and anhydrous methanol (0.6 mL) was added lithium borohydride (4 M in tetrahydrofuran, 3.5 mL, 16.00 mmol) at 0° C. and the mixture was heated to reflux for 2 hours. The mixture was then cooled to 0° C. and quenched with methanol until gas evolution ceased. The solution was warmed to ambient temperature then poured into water (50 mL). The aqueous layer was separated and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude alcohol (0.98 g), which was dissolved in anhydrous dimethylsulfoxide (6 mL), tert-butyl 5-chloro-2,4-difluorobenzoate (1.64 g, 6.60 mmol) and cesium carbonate (4.11 g, 12.6 mmol) was added. The reaction mixture was heated at 70° C. for 2 hours and then cooled to ambient temperature and diluted with water (60 mL) and extracted with ethyl acetate (4×20 mL). The combined organic layers were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes) to afford the title compound (0.681 g, 29%): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.7 Hz, 1H), 6.63 (d, J=12.1 Hz, 1H), 4.08 (t, J=6.6 Hz, 2H), 2.17-2.07 (m, 2H), 1.77-1.62 (m, 5H), 1.57 (s, 9H), 1.42-1.29 (m, 4H).

後処理

  1. temperaturethe mixture was heated
  2. temperatureto reflux for 2 hours
  3. customquenched with methanol until gas evolution
  4. temperatureThe solution was warmed to ambient temperature
  5. additionthen poured into water (50 mL)
  6. customThe aqueous layer was separated
  7. extractionextracted with diethyl ether (3×20 mL)
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried over anhydrous sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customto give the crude alcohol (0.98 g), which
  13. temperatureThe reaction mixture was heated at 70° C. for 2 hours
  14. temperaturecooled to ambient temperature
  15. extractionextracted with ethyl acetate (4×20 mL)
  16. washThe combined organic layers were washed with brine
  17. dry with materialdried over anhydrous sodium sulfate
  18. filtrationfiltered
  19. concentrationconcentrated in vacuo
  20. customThe residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes)

出典と根拠

ORDレコード
ord-68449667f48541c1a821455c8563875b
出典データセット
uspto-grants-2015_02
特許番号
US08952169B2

反応ノート

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