4-((1R,2S)-2-{2-[4-(ethylsulfonyl)-3-fluorophenoxy]ethyl}cyclopropyl)piperidine-1-carbonitrile → 4-((1S,2R)-2-{2-[4-(ethylsulfonyl)-3-fluorophenoxy]ethyl}cyclopropyl)-1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidine

HRID 1850748ノート

反応式

HRID 1850748 の反応式
[CH2:1]([S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][C@@H:13]2[CH2:15][C@@H:14]2[CH:16]2[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:26])(=[O:5])=[O:4])[CH3:2].[OH:27][NH:28][C:29](=N)[CH2:30][O:31][CH3:32]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH2:1]([S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][C@H:13]2[CH2:15][C@H:14]2[CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[O:27][N:28]=[C:29]([CH2:30][O:31][CH3:32])[N:23]=3)[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:26])(=[O:5])=[O:4])[CH3:2]

参加物

5

反応物 2

HCID 867111904-((1R,2S)-2-{2-[4-(ethylsulfonyl)-3-fluorophenoxy]ethyl}cyclopropyl)piperidine-1-carbonitrileHCID 178496050HCID 178496050、化合物

生成物 1

HCID 867111924-((1S,2R)-2-{2-[4-(ethylsulfonyl)-3-fluorophenoxy]ethyl}cyclopropyl)-1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidine

試薬・触媒・溶媒 2

HCID 3007855Zincchloride触媒HCID 8028Tetrahydrofuran溶媒

実験手順

To a solution of 4-((1R,2S)-2-{2-{4-(ethylsulfonyl)-3-fluorophenoxy]ethyl}cyclopropyl)piperidine-1-carbonitrile (Step D; 100 mg, 0.27 mmol) and N-hydroxy-2-methoxyacetimidamide (38 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (0.8 mL, 0.5 M in tetrahydrofuran, 0.4 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 30 min, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (10 g of silica gel) and eluted with a gradient of dichloromethane/CMA, 19:1, 500 mL; 4:1, 500 mL to provide the title compound. MS (ESI) m/z 468 [M+H]+.

後処理

  1. temperatureThe mixture was refluxed for 2 h
  2. concentrationconcentrated to dryness under reduced pressure
  3. dissolutionThe residue was dissolved in 2 mL of 4N HCl ethanol
  4. temperatureThe solution was refluxed for 30 min
  5. temperaturecooled to RT
  6. concentrationconcentrated to dryness under reduced pressure
  7. dissolutionThe residue was dissolved in methanol (5 mL)
  8. additionneutralized by the addition of excess potassium carbonate
  9. additionmixed silica gel (2 g)
  10. concentrationconcentrated to dryness under reduced pressure
  11. washeluted with a gradient of dichloromethane/CMA, 19:1, 500 mL

出典と根拠

ORDレコード
ord-60c62e7fa59f4c16a2b96da9c8ccfded
出典データセット
uspto-grants-2015_02
特許番号
US08957062B2

反応ノート

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