Malonic Acid → Nilotinib malonate

HRID 1528272Notes

Reaction equation

HRID 1528272 reaction equation
[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:46])(=[O:45])[CH2:41][C:42]([OH:44])=[O:43]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:46])(=[O:45])[CH2:41][C:42]([O-:44])=[O:43]

Participants

3

Reactant 2

HCID 867Malonic Acid2×HCID 644241Nilotinib2×

Product 1

HCID 86688198Nilotinib malonate

Conditions

Temperature
68 °C

Procedure

Nilotinib base Form A (3.00 g, 5.67 mmol) was dissolved in TFE (29 mL, 9.7V) at room temperature with stirring. Separately, malonic acid (0.62 g, 5.95 mmol, 1.05 mol eq), was mixed with TFE (3 mL) and heated to 68° C. to afford dissolution. The malonic acid solution was added to the solution of Nilotinib base in TFE at 68° C. and stirring was continued at the same temperature for 5 h. The heating source was removed and the mixture was allowed to cool to ambient temperature over a period of 30 min. Then, the mixture was transferred to the refrigerator and kept at 5° C. for 16 h. Methyl tert-butyl ether (“MTBE”) (30 mL) was then added and the resulting mixture was stirred at room temperature for about 20 min leading to the formation of a white precipitate. The precipitate was filtered and dried overnight in a vacuum oven (60° C.) to give Nilotinib malonate form I.

Workup

  1. customto afford
  2. dissolutiondissolution
  3. stirringstirring
  4. customThe heating source was removed
  5. temperatureto cool to ambient temperature over a period of 30 min
  6. waitkept at 5° C. for 16 h
  7. additionMethyl tert-butyl ether (“MTBE”) (30 mL) was then added
  8. stirringthe resulting mixture was stirred at room temperature for about 20 min
  9. filtrationThe precipitate was filtered
  10. customdried overnight in a vacuum oven (60° C.)

Sources & evidence

ORD record
ord-07e170d1e4124a3d94c9357d097b3848
Source dataset
uspto-grants-2015_07
Patent number
US09090598B2

Reaction notes

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