Ammonium Chloride → Duloxetine Hydrochloride

HRID 1987512Notes

Reaction equation

HRID 1987512 reaction equation
[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[Cl-:22].[NH4+]>CO>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=12)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[ClH:22]

Participants

4

Reactant 2

HCID 25517Ammonium ChlorideHCID 60835Duloxetine

Product 1

HCID 60834Duloxetine HydrochlorideYield 48%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
42.5 °C

Procedure

To (S)-(+)-N-methyl-3-(1-naphthaleneoxy)-3-(2-thienyl)propanamine free base (65 gm) prepared as above, methanol (520 ml) is added under stirring. To the clear solution at 20-25° C., ammonium chloride (12.3 gm) is added under stirring. The reaction mixture is stirred at 20-25° C. for 1.5 hours. The solution is heated to 40-45° C. and methanol is distilled out under vacuum, residue is degassed. To the residue, dichloromethane (650 ml) is added under stirring, at 25-30° C. and the clear solution is stirred for 30 minutes. Then dichloromethane layer is washed with D.M Water (2×130 ml). Organic layer (dichloromethane layer) is charcoalised at 25-30° C., filtered through Hyflo bed and dried over sodium sulfate. Dichloromethane is distilled out under vacuum at 40-45° C. and residual mass is degassed under vacuum. Acetone (195 ml) is added to the residual mass at 25-30° C. to get a slurry and the resultant slurry is gradually cooled to 5-10° C. and maintained for 1-2 hours. The product is filtered and washed with acetone (100 ml), dried in air oven at 65-70° C. for 2-3 hours to obtain pure duloxetine HCl (35 g, 100% ee).

Workup

  1. additionis added
  2. stirringunder stirring
  3. stirringThe reaction mixture is stirred at 20-25° C. for 1.5 hours
  4. distillationmethanol is distilled out under vacuum, residue
  5. customis degassed
  6. additionTo the residue, dichloromethane (650 ml) is added
  7. stirringunder stirring, at 25-30° C.
  8. stirringthe clear solution is stirred for 30 minutes
  9. washThen dichloromethane layer is washed with D.M Water (2×130 ml)
  10. customis charcoalised at 25-30° C.
  11. filtrationfiltered through Hyflo bed
  12. dry with materialdried over sodium sulfate
  13. distillationDichloromethane is distilled out under vacuum at 40-45° C.
  14. customresidual mass is degassed under vacuum
  15. additionAcetone (195 ml) is added to the residual mass at 25-30° C.
  16. customto get a slurry
  17. temperaturethe resultant slurry is gradually cooled to 5-10° C.
  18. temperaturemaintained for 1-2 hours
  19. filtrationThe product is filtered
  20. washwashed with acetone (100 ml)
  21. customdried in air oven at 65-70° C. for 2-3 hours

Sources & evidence

ORD record
ord-e4884f16cc764c5ba77dbf593ada55e4
Source dataset
uspto-grants-2009_06
Patent number
US07550605B2

Reaction notes

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