Triethylamine → 3-(4-(2-(2-(1H-Imidazol-4-yl)phenoxy)ethyl)phenyl)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)urea

HRID 1023837Notes

Reaction equation

HRID 1023837 reaction equation
C([N:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:42](Cl)([O:44]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[O:60]1[CH2:65][CH2:64][CH:63]([NH:66][OH:67])[CH2:62][CH2:61]1>ClCCl>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34][C:42](=[O:44])[N:66]([OH:67])[CH:63]3[CH2:64][CH2:65][O:60][CH2:61][CH2:62]3)=[CH:35][CH:36]=2)[N:22]=[CH:21]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 672072114-(2-(2-(1-Trityl-1H-imidazol-4-yl)phenoxy)ethyl)anilineHCID 82687656N-(tetrahydro-2H-pyran-4-yl)hydroxylamine

Product 1

HCID 1785220483-(4-(2-(2-(1H-Imidazol-4-yl)phenoxy)ethyl)phenyl)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)ureaYield 101.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethyl)aniline (113 mg, 0.217 mmol), triphosgene (21 mg, 0.07 mmol) and triethylamine (0.04 mL, 0.260 mmol) in dry dichloromethane (6 mL) was heated at reflux for 2 h and then cooled with an ice bath. To this mixture was added N-(tetrahydro-2H-pyran-4-yl)hydroxylamine (76 mg, 0.650 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the crude was dissolved in methanol (4 mL) and acetic acid (1 mL). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was basified with aqueous 10% NaOH and the aqueous layer extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using 5% MeOH/dichloromethane as an eluent at afford the desired product as a yellowish solid (30 mg, 33%). 1H NMR: 1.63 (d, 2H, J=10.4 Hz), 1.98-2.07 (m, 2H), 3.15 (t, 3H, J=5.6 Hz), 3.46 (t, 2H, J=11.6 Hz), 3.78 (s, 1H), 4.02 (dd, 2H, J=11.2 Hz, 4 Hz), 4.36-4.45 (m, 4H), 6.98-7.03 (m, 3H), 7.19-7.27 (m, 3H), 7.30-7.42 (m, 3H), 7.66 (s, 1H), 8.14 (s, 1H).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 2 h
  3. temperaturecooled with an ice bath
  4. customThe solvent was removed
  5. dissolutionthe crude was dissolved in methanol (4 mL)
  6. temperatureThe reaction mixture was heated at 80° C. for 2 h
  7. extractionthe aqueous layer extracted with ethyl acetate (2×30 mL)
  8. washThe combined organic extracts were washed with brine (15 mL)
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated
  11. customThe residue was purified by flash column chromatography

Sources & evidence

ORD record
ord-d66f7b1f9b0a47a8b74d581eea2bb9d5
Source dataset
uspto-grants-2014_05
Patent number
US08722720B2

Reaction notes

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