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

HRID 1170699Notes

Reaction equation

HRID 1170699 reaction equation
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

Participants

8

Reactant 6

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

Product 1

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

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

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. Takle, 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): δ1.25 (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]+.

Workup

  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

Sources & evidence

ORD record
ord-0babfee580c74473995c105f02b7f6ac
Source dataset
uspto-grants-2010_11
Patent number
US07825258B2

Reaction notes

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