Phosgene → [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-hydroxymethyl-piperidin-1-yl]-methanone

HRID 31520

Reaction equation

HRID 31520 reaction equation
[C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:22][C:21]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=3[O:41][CH2:42][CH3:43])=[N:20]2)=[CH:15][CH:14]=1.[OH:44][CH2:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:23]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[N:22]([C:1]([N:49]3[CH2:50][CH2:51][CH:46]([CH2:45][OH:44])[CH2:47][CH2:48]3)=[O:2])[C:21]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][C:32]=3[O:41][CH2:42][CH3:43])=[N:20]2)=[CH:17][CH:18]=1

Participants

7

Reactant 5

HCID 6371PhosgeneHCID 8471Triethylamine2×HCID 4207714-PiperidinemethanolHCID 516892Sodium BicarbonateHCID 101741684,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-1H-imidazole

Product 1

HCID 69273741[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-hydroxymethyl-piperidin-1-yl]-methanoneYield 79%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Phosgene (1.8 mL, 3.6 mmol, 1.9 M in toluene) was added dropwise to a cooled (0° C.) solution of triethylamine (0.57 mL, 4.0 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluro-phenyl)-4,5-dihydro-1H-imidazole (550 mg, 1.2 mmol, example 1) in methylene chloride (5.0 mL). The reaction mixture was stirred for 0.5 h at 0° C. The solvent was removed under reduced pressure. The residue was kept under high vacuum for 30 min and dissolved in methylene chloride (5.0 mL). Triethylamine (0.170, 1.2 mmol) and 4-(hydroxymethyl)piperidine (0.50 g, 4.4 mmol) were added. After 1 h, the reaction was worked up with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvents and flash chromatography of the residue over silica gel using 1-4% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-hydroxymethyl-piperidin-1-yl]-methanone (560 mg, 79%).

Workup

  1. customThe solvent was removed under reduced pressure
  2. waitThe residue was kept under high vacuum for 30 min
  3. dissolutiondissolved in methylene chloride (5.0 mL)
  4. waitAfter 1 h
  5. extractionextracted with methylene chloride
  6. washThe organic extracts were washed with brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. customEvaporation of the solvents and flash chromatography of the residue over silica gel using 1-4% methanol in methylene chloride

Sources & evidence

ORD record
ord-f971cb0a9c4040a1a2b5d6be83785893
Source dataset
uspto-grants-2008_09
Patent number
US07425638B2

Linked notes

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