Hydrochloric Acid → N-Benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide

HRID 1161307Notes

Reaction equation

HRID 1161307 reaction equation
ClC1C=C(C=CC=1[NH:11][C:12](=[O:38])[CH:13]([N:20]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=2[N:22]=C1C1C=NC(Cl)=CC=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)C(O)=O.[CH:39]1([CH:45]=O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.[CH3:47][O:48][C:49]1[N:57]=[C:56]([O:58][CH3:59])[CH:55]=[CH:54][C:50]=1[C:51](O)=O.[N+](CC1C=CC=CC=1)#[C-].Cl>CO.O1CCOCC1>[CH2:45]([NH:11][C:12](=[O:38])[CH:13]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[N:20]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=2[N:22]=[C:51]1[C:50]1[C:49]([O:48][CH3:47])=[N:57][C:56]([O:58][CH3:59])=[CH:55][CH:54]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 16275CyclohexanecarboxaldehydeHCID 82558Benzyl isocyanideHCID 8531782,6-Dimethoxypyridine-3-carboxylic acidHCID 441976913-Chloro-4-{2-[2-(6-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-benzoic acid2×

Product 1

HCID 66619365N-Benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamideYield 67%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (2.50 g, 10.24 mmol, 1.0 equiv; example 1, intermediate b) in methanol (30 mL) was added cyclohexanecarbaldehyde (1.15 g, 1.23 mL, 10.24 mmol, 1.0 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, 2,6-dimethoxy-nicotinic acid (1.88 g, 10.24 mmol, 1.0 equiv; [CAS RN 16727-43-8]) and isocyanomethyl-benzene (1.20 g, 1.25 mL, 10.24 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 (20 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/ethyl acetate to give 3.57 g (60%) of the title compound. MS (ES+): 522 (M+H).

Workup

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

Sources & evidence

ORD record
ord-6d2deffc43194fb5936c4980a70f8ddb
Source dataset
uspto-grants-2010_10
Patent number
US07816540B2

Reaction notes

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