Sodium Hydroxide → Nilotinib

HRID 1428266Notes

Reaction equation

HRID 1428266 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.S(Cl)(Cl)=O.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([NH2:42])[CH:33]=[C:34]([N:36]2[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]2)[CH:35]=1.[OH-].[Na+]>CN1CCCC1=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:42][C:32]2[CH:31]=[C:30]([C:29]([F:44])([F:43])[F:28])[CH:35]=[C:34]([N:36]3[CH:37]=[N:38][C:39]([CH3:41])=[CH:40]3)[CH:33]=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

6

Reactant 4

HCID 14798Sodium HydroxideHCID 24386Thionyl ChlorideHCID 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 90.2%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent3×

Conditions

Temperature
60 °C

Procedure

To a 1 liter reactor was fed 40 g of 4-methyl-3-(4-(pyridine-3-yl)pyrimidin-2-ylamino)benzoic acid (0.13 mol), 200 ml of N-methylpyrrolidone (NMP) (5V) and 13 ml of thionyl chloride (0.18 mol). The reactor was heated to 60° C. and maintained at 60° C. for 1.5 hr. After 1.5 hr of heating, 31.5 g of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzenamine (0.13 mol) was fed into the reactor. The reactor was then heated to 90° C., and maintained for 30 minutes at this temperature. Then 200 ml (5V) of water was added. The resulting mixture was maintained for 2 hours at 90° C. Then, an additional 240 ml (6V) of N-methylpyrrolidone was added, followed by 26.5 ml of sodium hydroxide (47% aqueous) to raise the pH to 6.5-7. The reactor was then cooled to 40° C. and maintained for 3 hours. The mixture was then filtered and the filter cake was washed with ethanol and water. The washed material was then dried in a vacuum tray oven overnight to provide dry Nilotinib base (62.1 g, Yield 90%)

Workup

  1. customTo a 1 liter reactor was fed
  2. temperaturemaintained at 60° C. for 1.5 hr
  3. temperatureAfter 1.5 hr of heating
  4. temperatureThe reactor was then heated to 90° C.
  5. temperaturemaintained for 30 minutes at this temperature
  6. temperatureThe resulting mixture was maintained for 2 hours at 90° C
  7. temperatureto raise the pH to 6.5-7
  8. temperatureThe reactor was then cooled to 40° C.
  9. temperaturemaintained for 3 hours
  10. filtrationThe mixture was then filtered
  11. washthe filter cake was washed with ethanol and water
  12. customThe washed material was then dried in a vacuum tray oven overnight

Sources & evidence

ORD record
ord-3ec1b9dd2c754d13831d71557b403c47
Source dataset
uspto-grants-2015_01
Patent number
US08937082B2

Reaction notes

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