Pyridine → (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)-4-benzylpiperazine

HRID 1375043Notes

Reaction equation

HRID 1375043 reaction equation
[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([OH:8])=O.N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[CH3:30][O:31][C:32]1[CH:51]=[CH:50][C:35]([CH2:36][C@@H:37]2[CH2:42][N:41]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:40][CH2:39][NH:38]2)=[CH:34][CH:33]=1>O1CCCC1.ClCCl.C(N(CC)CC)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:38]1[CH2:39][CH2:40][N:41]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][C@H:37]1[CH2:36][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:51][CH:50]=1)=[O:8]

Participants

8

Reactant 4

HCID 1049PyridineHCID 128893,5-Bis(trifluoromethyl)benzoic acidHCID 65578Oxalyl chlorideHCID 53781111(2R)-2-(4-methoxybenzyl)-4-benzylpiperazine

Product 1

HCID 53698566(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)-4-benzylpiperazineYield 80.1%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
55 °C

Procedure

To a solution of 3,5-bis(trifluoromethyl)benzoic acid (3.04 g) and pyridine (0.030 ml) in tetrahydrofuran (9 ml) was added dropwise oxalyl chloride. (1.80 g) over 5 minutes, and the reaction mixture was heated at 55° C. with stirring for one hour. After cooling, the solution was added dropwise to a solution of (2R)-2-(4-methoxybenzyl)-4-benzylpiperazine (3.47 g) and triethylamine (3.55 g) in dichloromethane (35 ml) below 5C over 30 minutes under nitrogen atmosphere. The reaction mixture was stirred at room temperature for one hour, and concentrated under reduced pressure. To the residue were added ethyl acetate (40 ml) and water (20 ml) with stirring. The organic layer was separated, washed with brine, and dried over magnesium sulfate. After removal of the solvent by evaporation, the resulting residue was purified by column chromatography on silica gel (70 g) using a mixed solvent of toluene and ethyl acetate (5:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)-4-benzylpiperazine (5.03 g) as syrup.

Workup

  1. temperatureAfter cooling
  2. stirringThe reaction mixture was stirred at room temperature for one hour
  3. concentrationconcentrated under reduced pressure
  4. additionTo the residue were added ethyl acetate (40 ml) and water (20 ml)
  5. stirringwith stirring
  6. customThe organic layer was separated
  7. washwashed with brine
  8. dry with materialdried over magnesium sulfate
  9. customAfter removal of the solvent
  10. customby evaporation
  11. customthe resulting residue was purified by column chromatography on silica gel (70 g)
  12. additionThe fractions containing the objective compound
  13. customwere collected
  14. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-08f2fb575a4b48ed9796c4d2dc55d3d5
Source dataset
uspto-grants-2007_01
Patent number
US07166598B2

Reaction notes

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