Hydrochloric Acid → N-Benzyl-2-cyclohexyl-2-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetamide

HRID 1099468ノート

反応式

HRID 1099468 の反応式
C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[NH2:15])(C)(C)C.[CH:17]1([CH:23]=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CO[C@H:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([OH:30])=O.[N+:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)#[C-].Cl.[CH3:47]O>O1CCOCC1>[CH2:39]([NH:37][C:28](=[O:30])[CH:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[N:15]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[N:7]=[C:6]1[C@H:23]([O:24][CH3:47])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1

参加物

8

反応物 6

HCID 313Hydrochloric AcidHCID 887MethanolHCID 16275CyclohexanecarboxaldehydeHCID 82558Benzyl isocyanideHCID 2724294(R)-(-)-alpha-methoxyphenylacetic acidHCID 53420357N2-(tert-Butoxycarbonyl)-4-fluoro-1,2-phenylenediamine

生成物 1

HCID 66810460N-Benzyl-2-cyclohexyl-2-[5-fluoro-2-((R)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetamide収率 69%

試薬・触媒・溶媒 1

HCID 312751,4-Dioxane溶媒

実験手順

To a solution of (2-amino-5-fluoro-phenyl)-carbamic acid tert-butyl ester (4.0 g, 17.68 mmol, 1.0 equiv; prepared as described in M. J. Bamford, M. J. Alberti, N. Bailey, S. Davies, D. K. Dean, A. Gaiba, S. Garland, J. D. Harling, D. K. Jung, T. A. Panchal, C. A. Parr, J. G. Steadman, A. K. Talde, J. T. Townsend, D. M. Wilson, J. Witherington Bioorg. Med. Chem. Lett. 2005, 15, 3402-3406) in methanol (50 mL) was added cyclohexanecarbaldehyde (1.98 g, 2.13 mL, 17.68 mmol, 1.0 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (R)-methoxy-phenyl-acetic acid (2.94 g, 17.68 mmol, 1.0 equiv; [CAS RN 3966-32-3]) and isocyanomethyl-benzene (2.07 g, 2.15 mL, 17.68 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (18 mL) was added and the reaction mixture stirred at rt overnight. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate to give 5.9 g (69%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 1.41 (t, J=7.5 Hz, 3H), 3.43 (s, 3H), 4.01 (q, J=7.5 Hz, 2H), 4.26 (q, J=7.5 Hz, 2H), 5.05 (s, 1H), 6.43-6.48 (m, 2H). MS (ISP): 486.4 [M+H]+.

後処理

  1. customprepared
  2. stirringstirring
  3. waitcontinued at rt for 2 h
  4. stirringthe reaction mixture stirred at rt overnight
  5. concentrationThe solution was concentrated by evaporation under reduced pressure
  6. additionthe pH adjusted to 9 by addition of a solution of 1 M NaHCO3
  7. extractionthe aqueous layer extracted with dichloromethane
  8. dry with materialThe combined organic phases were dried over MgSO4
  9. concentrationconcentrated by evaporation under reduced pressure
  10. customThe crude material was purified by silica column chromatography
  11. washeluting with a gradient of heptane (+1% triethylamine)/ethyl acetate

出典と根拠

ORDレコード
ord-8346a3fd58954485b083cce2b64369ab
出典データセット
uspto-grants-2012_03
特許番号
US08143422B2

反応ノート

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