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US 6,723,855 B2Granted
Method for synthesizing leflunomide
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsIlya Avrutov, Neomi Gershon, Anita Liberman
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Abstract
A process for synthesizing leflunomide from 5-methylisoxazole-4-carboxylic acid and 4-trifluoromethylaniline is provided in which the carboxylic acid group of 5-methylisoxazole-4-carboxylic acid is chlorinated, forming 5-methylisoxazole-4-carboxylic acid chloride. The acid chloride is then reacted without intermediate distillation with 4-trifluoromethylaniline in the presence of an alkali metal or alkaline-earth metal bicarbonate acid scavenger.
Claims26
A process for preparing leflunomide comprising the steps of
- a) chlorinating 5-methylisoxazole-4-carboxylic acid by contacting it with a chlorinating agent thereby forming crude 5-methylisoxazole-4-carboxylic acid chloride,
- b) optionally evaporating excess chlorinating agent or volatile byproducts of the chlorination under reduced pressure, whereby evaporation leaves a residue of unevaporated material containing 5-methylisoxazole-4-carboxylic acid chloride,
- c) contacting the so-formed crude 5-methylisoxazole-4-carboxylic acid chloride or residue with 4-trifluoromethylaniline in the presence of an alkali metal or alkaline-earth metal bicarbonate in an acylation solvent system comprising at least one solvent component selected from the group consisting of water, ethyl acetate, toluene and dimethyl acetamide, and
- d) isolating the leflunomide.
1 more element
Dependencies are inferred from the claim text.