Acetyl chloride → 1-[(4-Chlorophenyl)methyl]-1,4-diazepane

HRID 2119358Notes

Reaction equation

HRID 2119358 reaction equation
C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>CCO>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1

Participants

5

Reactant 3

HCID 6367Acetyl chlorideHCID 77231-Chloro-4-(chloromethyl)benzeneHCID 68163Hexahydro-1,4-diazepine

Product 1

HCID 156343771-[(4-Chlorophenyl)methyl]-1,4-diazepaneYield 54.2%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
25 °C

Procedure

Acetyl chloride (11.7 mL, 0.165 mol) was added to anhydrous EtOH (500 mL) and the mixture was stirred for 30 min at 25° C. Homopiperazine (15.0 g, 0.150 mol) was added and the mixture was heated to reflux for 4 h. 4-Chlorobenzyl chloride (13.96 g, 0.087 mol) was added and the reaction mixture was heated to reflux for 16 h before concentrating. The residue was dissolved in EtOAc (500 mL) and washed with 1N aqueous KOH (50 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (double separation. SiO2, 20×7 cm, 1PrOH—H2O—NH4OH, 80:12:6 to 70:20:10 gradient elution) afforded the desired product (10.6 g, 53.4%) and the dialkylated homopiperazine (2.36 g, 16.5%). GC/MS m/e 224 (M+, C12H17N2Cl).10% CH3OH—CH2Cl2); RPLC tR=5.96 min (>85%), 220 nm (Mm (Method B): ESI/MS m/e 498.3 (MH++H, C31H35N3O3).

Workup

  1. temperaturethe mixture was heated
  2. temperatureto reflux for 4 h
  3. temperaturethe reaction mixture was heated
  4. temperatureto reflux for 16 h
  5. concentrationbefore concentrating
  6. dissolutionThe residue was dissolved in EtOAc (500 mL)
  7. washwashed with 1N aqueous KOH (50 mL)
  8. extractionThe aqueous layer was extracted with EtOAc (200 mL)
  9. dry with materialThe combined organic layers were dried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customChromatography (double separation. SiO2, 20×7 cm, 1PrOH—H2O—NH4OH, 80:12:6 to 70:20:10 gradient elution)

Sources & evidence

ORD record
ord-2cad4e417b304170a49e5ee79dde87c0
Source dataset
uspto-grants-2004_02
Patent number
US06686353B1

Reaction notes

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