Hydrogen Bromide → Citalopram Hydrobromide

HRID 2218541Notes

Reaction equation

HRID 2218541 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.[BrH:28]>CS(C)=O.O.C(OCC)(=O)C.CC(C)=O>[CH3:21][N:22]([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)[O:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[CH:17][C:18]1=2)[CH3:27].[BrH:28]

Participants

9

Reactant 4

HCID 260Hydrogen BromideHCID 24758Sodium hydrideHCID 669603-Chloro-N,N-dimethyl-1-propanamineHCID 98561591-(4'-Fluorophenyl)-1,3-DihydroIsobenzofuran-5-Carbonitrile

Product 1

HCID 77995Citalopram Hydrobromide

Reagents, catalysts & solvents 4

HCID 180AcetoneSolventHCID 679Dimethyl SulfoxideSolvent2×HCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
10 °C

Procedure

To a mixture 5.42 g sodium hydride in 120 ml of dimethylsulfoxide, previously heated at 60° C. for 30 minutes, under nitrogen flow, a solution of 30 g of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile obtained in Example 2 in 75 ml of dimethylsulfoxide is added, without exceeding 25° C. The solution is maintained under stirring for 30 minutes and, in 10 minutes, 33 g of 3-(dimethylamino)propylchloride are added without exceeding 25° C. After about 2-hour stirring at 25° C., the mixture is cooled at 10° C. and 300 ml of water are added dropwise and then 120 ml of ethyl acetate. The mixture is stirred and diluted with 1650 ml of water and 120 ml of ethyl acetate. The mixture is let 1 hour under stirring, then the phases are separated; the organic one is collected and the aqueous one is washed with 3×150 ml of ethyl acetate. After separation of the phases, the aqueous one is discarded and the collected organic ones are washed with 900 ml of water. The organic phase is dehydrated with anhydrous Na2SO4 and is concentrated under vacuum at 50° C. until an oil is obtained, which is treated with 60 ml of acetone. The mixture is stirred in order to obtain a solution, that is cooled at 10° C. and treated with about 10 ml of 48% HBr in order to adjust the pH value from 9.8-9.5 to 7.0. After 1 hour-stirring at pH=7 constant, the solvent is evaporated under vacuum at 50° C. and the residue is treated with 100 ml of acetone. The suspension is stirred at 25° C. for 30 minutes, then it is cooled at 0-5° C. and it is let at cold for 15 hours. The product is filtered, washed with cold acetone (0-5° C.) and is dried under vacuum at 50° C. Thus 34.88 g of citalopram hydrobromide with a purity (HPLC)=99.15% are obtained.

Workup

  1. customwithout exceeding 25° C
  2. temperatureThe solution is maintained
  3. customwithout exceeding 25° C
  4. stirringAfter about 2-hour stirring at 25° C.
  5. stirringThe mixture is stirred
  6. waitThe mixture is let 1 hour
  7. stirringunder stirring
  8. customthe phases are separated
  9. customthe organic one is collected
  10. washthe aqueous one is washed with 3×150 ml of ethyl acetate
  11. customAfter separation of the phases
  12. washthe collected organic ones are washed with 900 ml of water
  13. concentrationis concentrated under vacuum at 50° C. until an oil
  14. customis obtained
  15. stirringThe mixture is stirred in order
  16. customto obtain a solution, that
  17. temperatureis cooled at 10° C.
  18. stirringAfter 1 hour-stirring at pH=7 constant
  19. customthe solvent is evaporated under vacuum at 50° C.
  20. additionthe residue is treated with 100 ml of acetone
  21. stirringThe suspension is stirred at 25° C. for 30 minutes
  22. temperatureit is cooled at 0-5° C.
  23. customcold for 15 hours
  24. filtrationThe product is filtered
  25. washwashed with cold acetone (0-5° C.)
  26. customis dried under vacuum at 50° C

Sources & evidence

ORD record
ord-9996d32a6c1347a684cd49d87ae49fbf
Source dataset
uspto-grants-2008_08
Patent number
US07411077B2

Reaction notes

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