The synthesis of zileuton involved conventional synthetic procedures starting with 2-acetylbenzo[b]thiophene. Treatment of a solution of 2-acetylbenzo[b]thiophene (I) in ethanol/pyridine (1:1) with hydroxylamine hydrochloride at room temperature provided the corresponding oxime (II). To the oxime (II) dissolved in ethanol was added borane:pyridine complex followed by the dropwise addition of 20% HCl in ethanol to provide the hydroxylamine (III), isolated by extraction after neutralization of the acidic mixture. The hydroxylamine (III) was converted to zileuton by either heating with trimethylsilylisocyanate in dioxane or by reacting with KOCN and aqueous HCl.
A new efficient synthesis of 2-acetylbenzothiophene (I), the key starting material for the previously reported synthesis of zileuton, has been described: Thiophenol (II) is dilithiated with butyllithium and tetramethylethylenediamine in cyclohexane to compound (III), which is then cyclized by successive treatments with DMF and chloroacetone (IV) in THF to afford (I) in high yield.