Triethylamine → Nilotinib

HRID 2368540Notes

Reaction equation

HRID 2368540 reaction equation
[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1.[CH3:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:31]=[C:32]([NH2:40])[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[CH:29]=1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:40][C:32]2[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=[C:30]([N:28]3[CH:27]=[N:26][C:25]([CH3:24])=[CH:29]3)[CH:31]=2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]1[N:13]=[CH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)[N:17]=1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 76257Diethyl cyanophosphonateHCID 104028804-Methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzoic acidHCID 120028253-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline

Product 1

HCID 644241NilotinibYield 56.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid (55 gm), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-benzenamine (45 gm), diethylcyanophosphonate (63 ml), triethylamine (78 ml) and N,N-dimethylformamide (1100 ml) were added at room temperature. The contents were heated to 60° C. and maintained for 13 hours at 60° C. The reaction mass was then cooled to room temperature and quenched with sodium bicarbonate solution (8%) and ethyl acetate. Then the layers were separated and ethyl acetate layer washed with sodium chloride solution. The separated ethyl acetate layer was then concentrated to obtain a residual solid. To the residual solid was added water (500 ml) and stirred for 30 minutes at room temperature. The separated solid was filtered and dried to obtain a solid. To the solid was added to teterahydrofuran (900 ml) and stirred for 30 minutes at 50 to 55° C. The teterahydrofuran solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added ethyl acetate (900 ml) and stirred for 1 hour at room temperature. The solid obtained was collected by filtration and dried to obtain 54 gm of nilotinib.

Workup

  1. temperaturemaintained for 13 hours at 60° C
  2. temperatureThe reaction mass was then cooled to room temperature
  3. customquenched with sodium bicarbonate solution (8%) and ethyl acetate
  4. customThen the layers were separated
  5. washethyl acetate layer washed with sodium chloride solution
  6. concentrationThe separated ethyl acetate layer was then concentrated
  7. customto obtain a residual solid
  8. filtrationThe separated solid was filtered
  9. customdried
  10. customto obtain a solid
  11. additionTo the solid was added to teterahydrofuran (900 ml)
  12. stirringstirred for 30 minutes at 50 to 55° C
  13. distillationThe teterahydrofuran solvent was distilled off under vacuum
  14. customto obtain a residual solid
  15. stirringstirred for 1 hour at room temperature
  16. customThe solid obtained
  17. filtrationwas collected by filtration
  18. customdried

Sources & evidence

ORD record
ord-d40d370001864dab8ae22c6752bb4029
Source dataset
uspto-grants-2014_04
Patent number
US08703788B2

Reaction notes

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