1,3-Dimethyl-2-imidazolidinone → Citalopram

HRID 990287Notes

Reaction equation

HRID 990287 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[CH2:12][O:11]2)=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl.CN1CCN(C)C1=O>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH2:12][O:11]1

Participants

8

Reactant 4

HCID 66611,3-Dimethyl-2-imidazolidinoneHCID 24758Sodium hydrideHCID 669603-Chloro-N,N-dimethyl-1-propanamineHCID 98561591-(4'-Fluorophenyl)-1,3-DihydroIsobenzofuran-5-Carbonitrile

Product 1

HCID 2771CitalopramYield 79.1%

Reagents, catalysts & solvents 3

HCID 74236Tetrabutylammonium BromideCatalystHCID 8028TetrahydrofuranSolvent2×HCID 15413tert-Butyl methyl etherSolvent

Procedure

60% Sodium hydride (0.96 g) was dispersed in THF (20 ml), and to this suspension was added dropwise a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (5.0 g) in THF (10 ml) at 40-50° C. under a nitrogen atmosphere. Thereto was added tetra n-butylammonium bromide (0.2 g), and a solution of 3-(dimethylamino)propyl chloride (3.4 g) in t-butyl methyl ether (18 ml) was added dropwise, which was followed by stirring for 10 min. Further, 1,3-dimethyl-2-imidazolidinone (26.1 g, 25 ml) was added and the mixture was stirred at 61-64° C. for 6 hr. The reaction mixture was poured into ice water (83 ml) and extracted 3 times with toluene (33 ml). The organic layer was extracted 3 times with 20% aqueous acetic acid (41 ml), and the obtained aqueous layer was neutralized with 25% aqueous sodium hydroxide solution (120 g) and extracted 3 times with toluene (40 ml). The obtained organic layer was washed with water, and the solvent was evaporated to give 1-(3-(dimethylamino)propyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (5.36 g, yield 79.1%).

Workup

  1. stirringthe mixture was stirred at 61-64° C. for 6 hr
  2. extractionextracted 3 times with toluene (33 ml)
  3. extractionThe organic layer was extracted 3 times with 20% aqueous acetic acid (41 ml)
  4. extractionextracted 3 times with toluene (40 ml)
  5. washThe obtained organic layer was washed with water
  6. customthe solvent was evaporated

Sources & evidence

ORD record
ord-a34516ff7e7647d8ad10707be358119f
Source dataset
uspto-grants-2002_10
Patent number
US06458975B1

Reaction notes

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