Synthesis
Step 2. Synthesis of 5-amino-3-isopropylisoxazole: Hydroxylamine hydrochloride (10.3 g, 148 mmol) was slowly added to a pre-cooled aqueous solution (73 mL) of NaOH (25.9 g, 645 mmol) under ice bath conditions. Subsequently, the resulting solution was added dropwise to a solution of crude 3-oxo-4-methylpentanenitrile while maintaining stirring. The reaction mixture was heated at 50 °C for 2.5 h. The formation of a yellow oily material with low density was observed during the reaction. Upon completion of the reaction, the reaction mixture was extracted with CHCl3 (3 x 100 mL) while hot without cooling. The organic phases were combined, dried with anhydrous MgSO4 and subsequently concentrated under reduced pressure. The resulting yellow oily solid was purified by a silica gel pad (eluent: 10% acetone/90% CH2Cl2) to afford the target product 5-amino-3-isopropylisoxazole as a yellow solid (11.3 g, 70% yield) with a melting point of 63-65 °C. TLC analysis showed an Rf value of 0.19 (eluent: 5% acetone/95% CH2Cl2).1H-NMR ( DMSO-d6) δ: 1.12 (d, J = 7.0 Hz, 6H), 2.72 (sept, J = 7.0 Hz, 1H), 4.80 (s, 2H), 6.44 (s, 1H).FAB-MS m/z (relative abundance): 127 ((M + H)+; 67%).
References
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1082 - 1105
[2] Patent: US2007/244120, 2007, A1. Location in patent: Page/Page column 13
[3] Synthesis (Germany), 2013, vol. 45, # 2, p. 171 - 173
[4] Patent: EP1047418, 2005, B1. Location in patent: Page/Page column 22
[5] Heterocycles, 1991, vol. 32, # 6, p. 1153 - 1158
