3-Phenylpropylamine → N-(3-Phenylpropyl)-3,5-bis(m-chlorophenyl)-4-(2-hydroxyethoxy)-benzamide

HRID 324072Notes

Reaction equation

HRID 324072 reaction equation
[C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:18][C:19](=O)[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C:23]([O:33][CH2:34][CH2:35][OH:36])=[C:22]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH:21]=1)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:19](=[O:18])[C:20]2[CH:21]=[C:22]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[C:23]([O:33][CH2:34][CH2:35][OH:36])=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1

Participants

5

Reactant 3

HCID 162593-PhenylpropylamineHCID 539906423,5-Bis-(m-chlorophenyl)4-(2-hydroxyethoxy)benzoic acid ethyl esterHCID 178418339Butyllithium

Product 1

HCID 22237459N-(3-Phenylpropyl)-3,5-bis(m-chlorophenyl)-4-(2-hydroxyethoxy)-benzamideYield 82.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a flamed dried round bottom flask with 3-phenyl-1-propylamine (0.404 mL, 2.84 mmol) and THF (5 mL) cooled to −78° C. was added n-BuLi (1.14 mL, 2.5 M in hexane, 2.84 mmol) dropwise over a 5 min. period. The resulting solution was stirred at this temperature for 0.5 h, warmed to 0° C. for 10 min., and then cooled back to −40° C. This lithiated amine solution was added dropwise to a solution (at −40° C.) of 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.350 g, 0.811 mmol) in THF (15 mL) over 5 min. The final mixture was stirred at −40° C. for 15 min. and then warmed to room temperature for 15 min. At this point, the reaction mixture was quenched with H2O (20 mL) and diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (20 to 40% EtOAc/hexane gradient) to afford the product (0.347 g, 82%) as a solid; 1H NMR (CDCl3) δ1.44-1.68 (bs, 1H), 2.01 (t, J=7.0 Hz, 2H), 2.74 (t, J=7.7 Hz, 2H), 3.27-3.46 (m, 4H), 3.53 (dd, J=7.7, 14.7 Hz, 2H), 5.94-6.08 (bs, 1H), 7.02-7.13 (m, 1H), 7.13-7.33 (m, 4H), 7.33-7.46 (m, 4H), 7.46-7.54 (m, 2H), 7.61 (s, 4H); mass spectrum [(+) APCI], m/z 520/522 (M+H)+.

Workup

  1. temperaturewarmed to 0° C. for 10 min.
  2. temperaturecooled back to −40° C
  3. temperaturewarmed to room temperature for 15 min
  4. customAt this point, the reaction mixture was quenched with H2O (20 mL)
  5. additiondiluted with EtOAc (200 mL)
  6. washThe organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL)
  7. dry with materialdried (MgSO4)
  8. concentrationAfter concentration
  9. customthe residue was purified by the Biotage Flash 40 apparatus (20 to 40% EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-8ae0368b737a4ead9a8939a54833bd53
Source dataset
uspto-grants-2001_04
Patent number
US06214877B1

Reaction notes

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