Norchlorcyclizine → tert-Butyl Cetirizine

HRID 1979057Notes

Reaction equation

HRID 1979057 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[OH-].[Na+].[Br-].C([NH3+])(C)(C)C>CC(=O)CC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 9340NorchlorcyclizineHCID 14798Sodium HydroxideHCID 12573419Tert-butyl 2-(2-chloroethoxy)acetateHCID 21584498Tert-butyl ammonium bromide

Product 1

HCID 9911366tert-Butyl CetirizineYield 96%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6569Methyl Ethyl KetoneSolvent

Conditions

Temperature
150 °C

Procedure

A suspension of 1-((4-chlorophenyl)phenylmethyl)piperazine (260 g, 0.9 mol), tert-butyl 2-(2-chloroethoxy)acetate (195 g, 1.0 mol), sodium hydroxide (106 g, 1 mol) and tert-butyl-ammonium bromide (“TABB”, 3.22 g, 0.01 mol, NOTE-TABB is a catalyst for this reaction) is dissolved in 2-butanone (“MEK”, 300 mL) heated to 150° C. and the water of reaction azeotroped over a period of about 4 hours. Heating is stopped and to the reaction mixture is added MEK (500 mL) added. The mixture is cooled to ambient, filtered and the solvent removed from the resulting solution by distillation under reduced pressure. The residue is dissolved in methyl tert-butylether (800 mL), washed with water (2×200 mL), saturated sodium chloride (2×100 mL) and the solvent removed under reduced pressure. The residue is treated with hexanes (1.8 mL) to afford tert-butyl (RS) 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate as a white crystalline powder (260 g, 96% yield).

Workup

  1. customfor this reaction)
  2. customazeotroped over a period of about 4 hours
  3. temperatureHeating
  4. additionis added MEK (500 mL)
  5. additionadded
  6. temperatureThe mixture is cooled to ambient,
  7. filtrationfiltered
  8. customthe solvent removed from the resulting solution by distillation under reduced pressure
  9. dissolutionThe residue is dissolved in methyl tert-butylether (800 mL)
  10. washwashed with water (2×200 mL), saturated sodium chloride (2×100 mL)
  11. customthe solvent removed under reduced pressure
  12. additionThe residue is treated with hexanes (1.8 mL)

Sources & evidence

ORD record
ord-5e1308a987db47838bb937ef0e79640b
Source dataset
uspto-grants-2001_05
Patent number
US06239277B1

Reaction notes

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