Acetone → Febuxostat

HRID 870886Notes

Reaction equation

HRID 870886 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[S:15][C:16]([C:20]([O:22]CC)=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].CC(C)=O.O.[OH-].[Li+].Cl>C(OCC)(=O)C.O>[CH3:19][C:17]1[N:18]=[C:14]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:3]([C:1]#[N:2])[CH:4]=2)[S:15][C:16]=1[C:20]([OH:22])=[O:21]

Participants

7

Reactant 4

HCID 180AcetoneHCID 313Hydrochloric AcidHCID 168937Lithium hydroxide, monohydrateHCID 98845495-Thiazolecarboxylic acid, 2-(3-cyano-4-(2-methylpropoxy)phenyl)-4-methyl-, ethyl ester

Product 1

HCID 134018FebuxostatYield 70.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (8.0 Kg), acetone (80 L), lithium hydroxide monohydrate (1.2 Kg), and water (12 L) were mixed and heated to reflux. The mixture was maintained under reflux until reaction completion. After the reaction was complete, the mass was cooled to about 25° C., ethyl acetate (120 L) was added, and pH was adjusted to about 1 to 2 with hydrochloric acid (3.2 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (80 L). The combined organic material was washed with water (3×80 L), and treated with activated carbon at about 50° C. The combined organic material was filtered, and the filtrate was evaporated completely under vacuum below 45° C. Acetonitrile (16 L) was added to the residue and the solvent was distilled. Acetonitrile (80 L) was added to the residue and the mixture was heated to about 65° C. and maintained for about 1 hour. The mass was cooled to about 30° C. and maintained for about 1 hour. The formed solid was filtered and washed with acetonitrile (32 L). The wet solid was dried at about 60° C. to a constant weight to yield 5.2 Kg of the title compound. Purity by HPLC: 99.9%.

Workup

  1. temperatureheated to reflux
  2. temperatureThe mixture was maintained
  3. temperatureunder reflux until reaction completion
  4. customThe organic layer was separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (80 L)
  6. washThe combined organic material was washed with water (3×80 L)
  7. additiontreated with activated carbon at about 50° C
  8. filtrationThe combined organic material was filtered
  9. customthe filtrate was evaporated completely under vacuum below 45° C
  10. additionAcetonitrile (16 L) was added to the residue
  11. distillationthe solvent was distilled
  12. additionAcetonitrile (80 L) was added to the residue
  13. temperaturethe mixture was heated to about 65° C.
  14. temperaturemaintained for about 1 hour
  15. temperatureThe mass was cooled to about 30° C.
  16. temperaturemaintained for about 1 hour
  17. filtrationThe formed solid was filtered
  18. washwashed with acetonitrile (32 L)
  19. customThe wet solid was dried at about 60° C. to a constant weight

Sources & evidence

ORD record
ord-ad39bd8495c1430b8016774a746978dc
Source dataset
uspto-grants-2015_03
Patent number
US08969582B2

Reaction notes

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