Phosgene → HCID 10008863, compound

HRID 1367702Notes

Reaction equation

HRID 1367702 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH:29]([CH3:31])[CH3:30])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(Cl)=[O:40].[C:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:45])[CH3:44].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:39]([N:49]3[CH2:50][CH2:51][N:46]([C:43](=[O:45])[CH3:44])[CH2:47][CH2:48]3)=[O:40])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH:29]([CH3:31])[CH3:30])=[N:9]2)=[CH:6][CH:7]=1

Participants

8

Reactant 5

HCID 6371PhosgeneHCID 8471TriethylamineHCID 837951-AcetylpiperazineHCID 516892Sodium BicarbonateHCID 5288630rel-(4R,5S)-4,5-Bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazole

Product 1

HCID 10008863HCID 10008863, compoundYield 98.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of cis-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (5.48 g, 12.03 mmol, example 2) in methylene chloride (100 mL) cooled to 0° C. were sequentially added triethylamine (11.8 mL, 84.21 mmol) and phosgene (30.53 mL, 60.15 mmol, 21% solution in toluene). The reaction mixture was stirred at 0° C. under argon for 0.5 h or until thin layer chromatography (silica gel, 100% ethyl acetate) showed no starting material left. The solvent and excess reagents were removed under reduced pressure, and the residue was dried under vacuum for 1 h. The residue was dissolved in methylene chloride (100 mL) then a solution of 1-acetylpiperazine (1.619 g, 12.63 mmol) in methylene chloride (10 mL) was added. The reaction mixture was stirred for 1 h at room temperature (or until no starting material was seen by thin layer chromatography). Saturated sodium bicarbonate solution (10 mL) was added. The product was extracted with methylene chloride (2×50 mL). The organic layers were washed with brine (1×20 mL), dried (anhydrous sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 100% ethyl acetate then with 5% methanol in ethyl acetate gave rac-1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone as an orange foam (˜7.2 g). It was recrystallized with methylene chloride and ethyl ether (6.721 g, white solids). Additional amount of rac-1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone (201 mg, tan color) was recovered from the mother liquor after purification by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 100% ethyl acetate then 5% methanol in ethyl acetate. Total yield: 6.922 g (94%). HR-MS (ES, m/z) calculated for C32H35N4O4Cl2 [(M+H)+] 609.2030, observed 609.2045.

Workup

  1. waitleft
  2. customThe solvent and excess reagents were removed under reduced pressure
  3. customthe residue was dried under vacuum for 1 h
  4. dissolutionThe residue was dissolved in methylene chloride (100 mL)
  5. extractionThe product was extracted with methylene chloride (2×50 mL)
  6. washThe organic layers were washed with brine (1×20 mL)
  7. dry with materialdried (anhydrous sodium sulfate)
  8. concentrationconcentrated in vacuo
  9. customPurification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel)
  10. washeluting with 100% ethyl acetate

Sources & evidence

ORD record
ord-e8f98c00e3a94c929c03e1f29b9b9238
Source dataset
uspto-grants-2011_02
Patent number
US07893278B2

Reaction notes

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