Lactic Acid → Panobinostat lactate

HRID 1669861Notes

Reaction equation

HRID 1669861 reaction equation
[OH:1][NH:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:25])=[CH:8][CH:7]=1.[C:27]([OH:32])(=[O:31])[CH:28]([CH3:30])[OH:29]>O>[C:27]([OH:32])(=[O:31])[CH:28]([CH3:30])[OH:29].[OH:1][NH:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:25])=[CH:8][CH:7]=1

Participants

4

Reactant 2

HCID 612Lactic AcidHCID 6918837Panobinostat

Product 1

HCID 23725423Panobinostat lactate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
65 °C

Procedure

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base (10.0 g) is placed in a 4-necked reaction flask with mechanical stirrer. Demineralized water (110.5 g) is added, and the suspension is heated to 65° C. (inner temperature) within 30 minutes. The DL-lactic acid solution is added to this suspension during 30 min at 65° C. During the addition of the lactate salt solution, the suspension converted into a solution. The addition funnel is rinsed with demineralized water (9.1 g), and the solution is stirred at 65° C. for an additional 30 minutes. The solution is cooled down to 45° C. (inner temperature) and seed crystals (10 mg N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate monohydrate) are added at this temperature. The suspension is cooled down to 33° C. and is stirred for additional 20 hours at this temperature. The suspension is re-heated to 65° C., stirred for 1 hour at this temperature and is cooled to 33° C. within 1 hour. After additional stirring for 3 hours at 33° C., the product is isolated by filtration, and the filter cake is washed with demineralized water (2×20 g). The wet filter-cake is dried in vacuo at 50° C. to obtain the anhydrous N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate salt as a crystalline product. The product is identical to the monohydrate salt (form HA) in HPLC and in 1H-NMR, with the exception of the integrals of water signals in the 1H-NMR spectra.

Workup

  1. washThe addition funnel is rinsed with demineralized water (9.1 g)
  2. temperatureThe solution is cooled down to 45° C. (inner temperature) and seed crystals (10 mg N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide lactate monohydrate)
  3. additionare added at this temperature
  4. temperatureThe suspension is cooled down to 33° C.
  5. stirringis stirred for additional 20 hours at this temperature
  6. temperatureThe suspension is re-heated to 65° C.
  7. stirringstirred for 1 hour at this temperature
  8. temperatureis cooled to 33° C. within 1 hour
  9. stirringAfter additional stirring for 3 hours at 33° C.
  10. customthe product is isolated by filtration
  11. washthe filter cake is washed with demineralized water (2×20 g)
  12. filtrationThe wet filter-cake
  13. customis dried in vacuo at 50° C.

Sources & evidence

ORD record
ord-45f9d197d33f457085be3692daadd6b3
Source dataset
uspto-grants-2011_08
Patent number
US07989639B2

Reaction notes

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