Hydrochloric Acid → Tivozanib hydrochloride anhydrous

HRID 1375159Notes

Reaction equation

HRID 1375159 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:31]=[C:30]([CH3:32])[O:29][N:28]=1)=[O:25].Cl.C(O)CC>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:31]=[C:30]([CH3:32])[O:29][N:28]=1)=[O:25]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 10311-PropanolHCID 9911830Tivozanib

Product 1

HCID 21079505Tivozanib hydrochloride anhydrousYield 167.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

N-{2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea (2 g) produced in Production Example was added to and was completely dissolved in N,N-dimethylformamide (10 mL) at 80° C. The solution was allowed to cool to room temperature, and 12 N hydrochloric acid (202 mL) was then added thereto, followed by stirring for one hr. The reaction solution was heated to 80° C., 1-propanol (60 mL) of 80° C. was added thereto, and the mixture was stirred at 80° C. After the precipitation of crystals was confirmed, the solution was cooled to 5° C. and was stirred at that temperature overnight. The resultant precipitate was collected by filtration, and the filtered product was dried under the reduced pressure to give a form II crystal of N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl)urea hydrochloride (1.81 g, yield 83.8%).

Workup

  1. additionwas added to and
  2. temperatureThe reaction solution was heated to 80° C.
  3. stirringthe mixture was stirred at 80° C
  4. customAfter the precipitation of crystals
  5. temperaturethe solution was cooled to 5° C.
  6. stirringwas stirred at that temperature overnight
  7. filtrationThe resultant precipitate was collected by filtration
  8. customthe filtered product was dried under the reduced pressure

Sources & evidence

ORD record
ord-18c1cb1db1c34868af15b3635fb200af
Source dataset
uspto-grants-2007_01
Patent number
US07166722B2

Reaction notes

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