Dimethyl Sulfoxide → Lenvatinib

HRID 557487Notes

Reaction equation

HRID 557487 reaction equation
[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](Cl)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14]([NH2:16])=[O:15].CS(C)=O.[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:31].CC(C)([O-])C.[K+]>O.O.CC(C)=O>[Cl:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:32][CH:33]1[CH2:34][CH2:35]1)=[O:31])[O:28][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:14]([NH2:16])=[O:15])[CH:5]=2)[N:10]=[CH:9][CH:8]=1

Participants

7

Reactant 4

HCID 679Dimethyl SulfoxideHCID 229364184-Chloro-7-methoxyquinoline-6-carboxamideHCID 23135084ME-92HCID 23665647Potassium tert-butoxide

Product 1

HCID 9823820LenvatinibYield 96.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 18366337Propan-2-one--water (1/1)Solvent2×

Conditions

Temperature
20 °C

Procedure

In a reaction vessel were placed 7-methoxy-4-chloro-quinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) in that order, under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes, the temperature was raised to 65° C. over a period of 2.5 hours. After stirring at the same temperature for 19 hours, 33% (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours. Upon completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours, and 33% (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or higher over a period of 1 hour. After then stirring at 40° C. for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were washed with 33% (v/v) acetone water (33.3 L), water (66.7 L) and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum drier to give 7.78 kg of the title compound (96.3% yield).

Workup

  1. customIn a reaction vessel were placed
  2. temperaturethe temperature was raised to 65° C. over a period of 2.5 hours
  3. stirringAfter stirring at the same temperature for 19 hours
  4. additionUpon completion of the dropwise addition
  5. stirringthe mixture was stirred at 60° C. for 2 hours
  6. stirringAfter then stirring at 40° C. for 16 hours
  7. filtrationthe precipitated crystals were collected by filtration
  8. filtrationfilter
  9. washthe crystals were washed with 33% (v/v) acetone water (33.3 L), water (66.7 L) and acetone (50.0 L) in that order
  10. customThe obtained crystals were dried at 60° C. for 22 hours

Sources & evidence

ORD record
ord-fca3682495fc4aea9a33b2b7015d0e59
Source dataset
uspto-grants-2011_11
Patent number
US08058474B2

Reaction notes

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