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

HRID 1281389Notes

Reaction equation

HRID 1281389 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) δ 1.44-1.68 (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-25cca4d58f7f4fd9b60c7540f54b7ff8
Source dataset
uspto-grants-2002_09
Patent number
US06451827B2

Reaction notes

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