Water → Cabozantinib

HRID 331213Notes

Reaction equation

HRID 331213 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:23]=[C:22]2[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:23]=[C:22]2[O:31][C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[CH2:13][CH2:12]2)=[O:15])=[CH:36][CH:37]=1

Participants

6

Reactant 4

HCID 962Water2×HCID 11430Potassium CarbonateHCID 115945434-[(6,7-Dimethoxyquinolin-4-yl)oxy]anilineHCID 580832671-[(4-Fluorophenyl)carbamoyl]cyclopropanecarbonyl chloride

Product 1

HCID 25102847Cabozantinib

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
22.5 °C

Procedure

The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg) and potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg) at a rate such that the batch temperature did not exceed 30° C. When the reaction was complete (in typically 10 minutes), water (74.0 kg) was added. The mixture was stirred at 15-30° C. for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a premade solution of THF (11.0 kg) and water (24.0 kg), and dried at approximately 65° C. under vacuum for approximately 12 hours to afford the title compound (free base, 5.0 kg). 1H NMR (400 MHz, d6-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.

Workup

  1. customdid not exceed 30° C
  2. customin typically 10 minutes
  3. additionwas added
  4. customwhich resulted in the precipitation of the product
  5. filtrationThe product was recovered by filtration
  6. washwashed with a premade solution of THF (11.0 kg) and water (24.0 kg)
  7. customdried at approximately 65° C. under vacuum for approximately 12 hours

Sources & evidence

ORD record
ord-954002d8875b48e2b4619c93852b9b87
Source dataset
uspto-grants-2014_11
Patent number
US08877776B2

Reaction notes

Loading…