Bulk Synthesis of Thermally Unstable 5-Amino-3-methylisoxazole Using Silica Coated Magnetite Nanoparticles (Fe3O4@SiO2)

Abstract

5-Amino-3-methylisoxazole is an important intermediate in medicinal chemistry. Bulk scale synthesis of it is reported and the reaction yields are typically around 40 %. The reaction of 3-aminocrotonitrile and hydroxylamine hydrochloride in aqueous environment in about 12 h at room temperature results in 5-amino-3-methylisoxazole. This simple one pot synthesis has an issue, which contributes to lower reaction yields. The melting point of 5-amino-3-methylisoxazole is 83-85 °C, but around 70 °C it can rapidly decompose causing an explosion. Hence, this molecule is synthesized by maintaining reaction temperature at 0-25 °C. Due to exothermic nature of the reaction, maintenance of lower temperature is mandatory. Due to lower reaction temperature, this reaction yields are usually low. Though these kind of lower yields are reported for synthesis of this class of compounds, attempts to improve the reaction yields are sparse. We report silica coated magnetic nanoparticle (Fe₃O₄@SiO₂) as an inert surface for preparation of 5-amino-3-methylisoxazole. The yield of reaction is around 80 %, almost double the reported yield and it is enabled by the 40 nm Fe₃O₄@SiO₂ particles. The 40 nm Fe₃O₄@SiO₂ are synthesized by modification to the famous “Stober” protocol. The obtained 40 nm particles contain intermittent particles with about 200 nm as reported in literature. Though isolation of 40 nm size magnetic nanoparticles in reactions is difficult, presence of about 200 nm size Fe₃O₄@SiO₂ is enabling for easy isolation. The work up of reaction is simple isolation of Fe₃O₄@SiO₂ by magnet, basification of reaction mixture to pH 10, dissolving the precipitated solid in diethyl ether, removal of ether to obtain crude 5-amino-3-methylisoxazole, which was recrystallized using distilled water. This protocol paves way for simple synthesis of related isoxazoles, which are increasingly forming base structure for many drugs and medicinal chemistry leads.