Dimethyl Sulfoxide → Citalopram

HRID 990291Notes

Reaction equation

HRID 990291 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.CS(C)=O>C1COCC1.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

7

Reactant 4

HCID 679Dimethyl SulfoxideHCID 24758Sodium hydrideHCID 669603-Chloro-N,N-dimethyl-1-propanamineHCID 98561591-(4'-Fluorophenyl)-1,3-DihydroIsobenzofuran-5-Carbonitrile

Product 1

HCID 2771CitalopramYield 61.1%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 15413tert-Butyl methyl etherSolvent

Procedure

To a suspension of 60% sodium hydride (4.2 g) dispersed in THF (135 ml) was added dropwise at 40-50° C. a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (21.6 g) in THF (40 ml). The mixture was stirred at the same temperature for 30 min and a solution of 3-dimethylaminopropyl chloride (14.4 g) in t-butyl methyl ether (60 ml) was added dropwise. The mixture was stirred for 10 min and dimethyl sulfoxide (135 ml) was added dropwise. The mixture was stirred at 60-70° C. for 5 hr. The reaction mixture was poured into ice water (800 ml) and extracted 3 times with toluene (250 ml). The organic layer was extracted twice with 20% aqueous acetic acid solution (250 ml). The aqueous layer was neutralized, extracted twice with toluene (250 ml) and washed with water. The solvent was evaporated to give 1-(3-(dimethylamino)propyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (17.9 g, 61.1%).

Workup

  1. stirringThe mixture was stirred for 10 min
  2. stirringThe mixture was stirred at 60-70° C. for 5 hr
  3. extractionextracted 3 times with toluene (250 ml)
  4. extractionThe organic layer was extracted twice with 20% aqueous acetic acid solution (250 ml)
  5. extractionextracted twice with toluene (250 ml)
  6. washwashed with water
  7. customThe solvent was evaporated

Sources & evidence

ORD record
ord-be26b363d7d3438e89f54e4a4e8a796c
Source dataset
uspto-grants-2002_10
Patent number
US06458975B1

Reaction notes

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