Ammonia → Rotigotine

HRID 875251Notes

Reaction equation

HRID 875251 reaction equation
O.[CH3:2][CH2:3][CH2:4][N:5]([C@@H:13]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:16]=2[CH2:15][CH2:14]1)[CH2:6][CH2:7][C:8]1[S:12][CH:11]=[CH:10][CH:9]=1.Cl.N>C1CCCCC1>[CH3:2][CH2:3][CH2:4][N:5]([C@@H:13]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:16]=2[CH2:15][CH2:14]1)[CH2:6][CH2:7][C:8]1[S:12][CH:11]=[CH:10][CH:9]=1

Participants

5

Reactant 3

HCID 222AmmoniaHCID 962WaterHCID 180335Rotigotine hydrochloride

Product 1

HCID 59227RotigotineYield 94.4%

Reagents, catalysts & solvents 1

HCID 8078CyclohexaneSolvent

Conditions

Temperature
60 °C

Procedure

Water (295 g) and rotigotine hydrochloride (120 g) followed by aqueous ammonia (25%, 111 g) and cyclohexane (295 g) are heated to reflux and agitated for 30-50 minutes. The mixture was cooled to 55-65° C. and the phases separated. Water (250 mL) is charged and the batch is heated to reflux for 30-50 minutes. The batch is cooled to 55-65° and the phases separated. The batch is then heated to reflux and cyclohexane/water is distilled until no further water is collected. The batch is then cooled to 70-78° C. If the volume of cyclohexane distilled off exceeds 15 mL then an equal amount to the cyclohexane that has been distilled off is charged to the batch. The organic phase is filtered through activated carbon and celite rinsing with cylohexane (110 g). The filterate was adjusted to 60-70° C. The batch is agitated at this temperature for 30-50 minutes. The batch is then cooled to 54-60° C. and rotigotine seed was added. After 15 minutes. The batch temperature is decreased to 37° C. in 5° C. intervals every 60 minutes. After 1 h stirring at 37° C. the batch is cooled to 25° C. and held 1 h at this temperature. The batch is then cooled and stirred at 6-12° C. for at least two hours. The slurry was then filtered and washed with cyclohexane (48 g). 101.5 g of rotigotine is obtained.

Workup

  1. temperatureare heated
  2. temperatureto reflux
  3. customthe phases separated
  4. additionWater (250 mL) is charged
  5. temperaturethe batch is heated
  6. temperatureto reflux for 30-50 minutes
  7. temperatureThe batch is cooled to 55-65°
  8. customthe phases separated
  9. temperatureThe batch is then heated
  10. temperatureto reflux
  11. distillationcyclohexane/water is distilled until no further water
  12. customis collected
  13. temperatureThe batch is then cooled to 70-78° C
  14. distillationIf the volume of cyclohexane distilled off
  15. distillationan equal amount to the cyclohexane that has been distilled off
  16. additionis charged to the batch
  17. filtrationThe organic phase is filtered through activated carbon and celite
  18. washrinsing with cylohexane (110 g)
  19. customwas adjusted to 60-70° C
  20. stirringThe batch is agitated at this temperature for 30-50 minutes
  21. temperatureThe batch is then cooled to 54-60° C.
  22. additionrotigotine seed was added
  23. waitAfter 15 minutes
  24. customis decreased to 37° C. in 5° C.
  25. customevery 60 minutes
  26. stirringAfter 1 h stirring at 37° C. the batch
  27. temperatureis cooled to 25° C.
  28. waitheld 1 h at this temperature
  29. temperatureThe batch is then cooled
  30. stirringstirred at 6-12° C. for at least two hours
  31. filtrationThe slurry was then filtered
  32. washwashed with cyclohexane (48 g)

Sources & evidence

ORD record
ord-20fd4bc64f9f4a2ba2eb8f95a26cedb2
Source dataset
uspto-grants-2015_03
Patent number
US08981121B2

Reaction notes

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