Romazarit (sodium salt) is prepared by a 7-step process from 4-chlorobenzoic acid, ethyl 2-chloroacetoacetate (VIII) and ethyl 2-methyl 2-hydroxypropionate (X). Reaction of the sodium salt of 4-chlorobenzoic acid (I) with ethyl 2-chloroacetoacetate (VIII) affords ethyl 3-oxo-2-(4-chlorophenylcarboxy)butyrate (II). Cyclization of (II) to ethyl 2-(4-chlorophenyl)-4-methyloxazole-5-carboxylate (III) is accomplished by treatment with formamide (IX)/sulfuric acid. Reduction of the ester (III) with lithium aluminum hydroxide in tetrahydrofuran yields 2-(4-chlorophenyl)-4-methyl-5-oxazolemethanol (IV). Chlorination of alcohol (IV) with thionyl chloride followed by reaction of crude chloromethyloxazole (V) with the sodium alkoxide derivative of ethyl 2-methyl-2-hydroxypropionate (X) yields ethyl [2-[(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionate (VI). Hydrolysis of the ester (VI), acidification and recrystallization affords Ro 31-3948 (VII) as a white solid, which is converted to the sodium salt by treatment with sodium isopropoxide in isopropanol.
A new synthesis of romazarit sodium has been published: By reaction of 2-(4-chlorophenyl)-4-methyl-5-oxazolemethanol (I) with acetone, chloroform and NaOH at reflux temperature. Compound (I) is already known (see original monograph). Romazarit sodium represents a novel type of antiinflammatory drug with oral activity in models of chronic inflammation, in which it has shown clinical and biochemical effects. Romazarit sodium is now in phase II trials in patients with rheumatoid arthritis.