Potassium Carbonate → Cabozantinib

HRID 2201895Notes

Reaction equation

HRID 2201895 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+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][C:22]4[C:21]5[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=5)[N:25]=[CH:24][CH:23]=4)=[CH:33][CH:34]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1

Participants

6

Reactant 3

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

Product 1

HCID 25102847Cabozantinib

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×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 compound 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30° C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25° C. for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25° C. and then at approximately 45° C. under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).

Workup

  1. customdid not exceed 30° C
  2. additionwas added
  3. customwhich resulted in the precipitation of the product
  4. filtrationThe product was recovered by filtration
  5. washwashed with a pre-made solution of THF (68.6 kg) and water (256 L)
  6. customdried first on
  7. filtrationa filter under nitrogen at approximately 25° C.

Sources & evidence

ORD record
ord-d151ae8cf58041d4b20877e033a18cc4
Source dataset
uspto-grants-2016_06
Patent number
US09365516B2

Reaction notes

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