Leflunomide can be obtained by several related ways: 1) The reaction of diketene (I) with 4-(trifluoromethyl)-aniline (II) in hot acetonitrile gives N-[4-(trifluoro-methyl) phenyl]acetoacetamide (III) , which by reaction with triethyl orthoformate (IV) in refluxing acetic anhydride yields the corresponding ethoxymethylene derivative (V). Finally, this compound is cyclized with hydroxylamine in refluxing ethanol/water. 2) The reaction of ethyl acetoacetate (VI) with triethyl orthoformate (IV) as before gives the corresponding ethoxymethylene derivative (VII), which by cyclization with hydroxylamine as before affords 5-methylisoxazole-4-carboxylic acid ethyl ester (VIII). The hydrolysis of (VIII) under acidic conditions yields the free acid (IX), which is converted into the acid chloride (X) by standard methods. Finally, this compound is condensed with 4-(trifluoro-methyl)aniline (II) by means of triethylamine in acetonitrile. 3) The formation of leflunomide from acid (IX) or its derivatives such as ethyl (VIII) or other esters can also be performed through other standard procedures of amide formation. 4) The N-[4-(trifluoromethyl)phenyl]acetoacetamide (III) can also be obtained by reaction of 4-(trifluoro-methyl) aniline (II) with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (XI) in refluxing xylene.
Treatment of veratrole (I) with aqueous HNO3 and H2SO4 yields 1,2-dinitrobenzene derivative (II), which is then converted into diamine (III) by hydrogenation over Pd/C in HOAc/EtOH or over PtO2. Finally, reaction of diamine (III) with phenyl glyoxal (IV) in EtOH and HOAc or HCl affords the desired product.