Ammonia → Citalopram Hydrobromide

HRID 840347Notes

Reaction equation

HRID 840347 reaction equation
CC1(C)CO[C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12]([CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:11][CH2:10]3)=[N:3]1.P(Cl)(Cl)(Cl)=O.N.[BrH:36]>N1C=CC=CC=1.CC(C)=O.O>[CH3:27][N:26]([CH2:25][CH2:24][CH2:23][C:12]1([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[O:11][CH2:10][C:9]2[CH:8]=[C:7]([C:4]#[N:3])[CH:15]=[CH:14][C:13]1=2)[CH3:28].[BrH:36]

Participants

8

Reactant 4

HCID 222AmmoniaHCID 260Hydrogen BromideHCID 24813Phosphorus oxychlorideHCID 112232084,4-Dimethyl-2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]oxazoline

Product 1

HCID 77995Citalopram Hydrobromide

Reagents, catalysts & solvents 3

HCID 180AcetoneSolventHCID 962WaterSolventHCID 1049PyridineSolvent

Conditions

Temperature
115.5 °C

Procedure

To a stirred solution of 4,4-dimethyl-2-[1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]oxazoline (287 g, 0.724 mol) in pyridine (1000 ml), at 5° C., phosphorous oxychloride (135 ml, 1.474 mol) is slowly added while keeping the temperature at 5 to 10° C. The mixture is heated at reflux (115-116° C.) for 3 to 4 hours. The mixture is cooled to about 10° C. and treated with deionized water (3200 mL), and the pH is adjusted to about pH 9 by addition of 28% aqueous ammonia (800 ml). The product is extracted with of toluene (1500+1000+500+500 ml) and the combined organic phases are decoloured with charcoal. The organic phase is concentrated under reduced pressure at 60-70° C. to give an oily residue to which acetone (3000 ml) is added. The acetone solution is cooled to 10° C. and treated with 60 ml 48% HBr to a pH value of 4-5. The solvent is evaporated under reduced pressure and the residue is taken up in acetone (800 ml). The mixture is heated to 40-50° C. and thereafter cooled to 5° C. After 15 hours at 5° C. the product is filtered off, washed with cold acetone (500 ml) and dried in vacuo at 50° C. 175-180 g of citalopram hydrobromide with a purity (HPLC, peak area)≧90% is obtained.

Workup

  1. customat 5 to 10° C
  2. temperatureThe mixture is heated
  3. temperatureThe mixture is cooled to about 10° C.
  4. extractionThe product is extracted with of toluene (1500+1000+500+500 ml)
  5. concentrationThe organic phase is concentrated under reduced pressure at 60-70° C.
  6. customto give an oily residue to which acetone (3000 ml)
  7. additionis added
  8. customThe solvent is evaporated under reduced pressure
  9. temperatureThe mixture is heated to 40-50° C.
  10. temperaturecooled to 5° C
  11. filtrationAfter 15 hours at 5° C. the product is filtered off
  12. washwashed with cold acetone (500 ml)
  13. customdried in vacuo at 50° C

Sources & evidence

ORD record
ord-cae0ad35add24f8cb29e7bae85aa9222
Source dataset
uspto-grants-2002_04
Patent number
US06365747B1

Reaction notes

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