Hydrochloric Acid → 2-[2-(3-Chloro-benzyl)-5-fluoro-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide

HRID 1678811Notes

Reaction equation

HRID 1678811 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)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl[C:26]1[CH:27]=[C:28]([CH2:32][C:33]([OH:35])=O)[CH:29]=[CH:30][CH:31]=1.[CH:36]1([N+:42]#[C-])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[ClH:44]>CO.O1CCOCC1>[Cl:44][C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:23][C:6]1[N:15]([CH:32]([CH:28]2[CH2:27][CH2:26][CH2:31][CH2:30][CH2:29]2)[C:33]([NH:42][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[N:7]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 158793-Chlorophenylacetic acidHCID 16275CyclohexanecarboxaldehydeHCID 79129Cyclohexyl isocyanideHCID 53420357N2-(tert-Butoxycarbonyl)-4-fluoro-1,2-phenylenediamine

Product 1

HCID 673748972-[2-(3-Chloro-benzyl)-5-fluoro-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamideYield 3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of (2-amino-5-fluoro-phenyl)-carbamic acid tert-butyl ester (33.94 mg, 0.15 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 (2.0 mL) was added cyclohexanecarbaldehyde (25.80 mg, 27.08 μL, 0.23 mmol, 1.5 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (3-chloro-phenyl)-acetic acid (34.12 mg, 0.20 mmol, 1.33 equiv; [CAS RN 1878-65-5]) and cyclohexyl isocyanide (16.38 mg, 18.41 μL, 0.15 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 (0.2 mL) was added and the reaction mixture stirred at rt overnight. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 2.1 mg (3%) of the title compound. MS (ISP): 482.3 [M+H]+.

Workup

  1. customprepared
  2. stirringstirring
  3. waitcontinued at rt for 2 h
  4. stirringthe reaction mixture stirred at rt overnight
  5. customRemoval of the solvent mixture
  6. customunder reduced pressure and purification by preparative HPLC on reversed phase
  7. washeluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-41d26d3b099141c0b33940b7f4391a5f
Source dataset
uspto-grants-2011_08
Patent number
US08008503B2

Reaction notes

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