Synthesis
Under argon protection, 500 mg of hydroxyphthalimide (Aldrich) was dissolved in 5 mL of dimethylformamide, followed by the addition of 0.44 mL of 1-iodopentane (Aldrich) and 0.5 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (Aldrich) in a slow dropwise manner. The reaction mixture was stirred at 60 °C for 2 h. When the reaction was complete, it was cooled to room temperature and the reaction was quenched by the addition of 2N hydrochloric acid solution. The reaction solution was diluted with 20 mL of ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with the eluent of ethyl acetate/hexane (1:5), and 707 mg of the target compound was obtained after drying (yield: 99%). The compound was dissolved in 5 mL of dichloromethane and 0.15 mL of methylhydrazine (TCI) was slowly added at 0 °C. The reaction solution was stirred at room temperature for 2 hours and then cooled to 0°C again. The resulting solid was collected by filtration and 1 mL of 4 M dioxane hydrochloride solution (Aldrich) was added to the filtrate, filtered and dried to give 414 mg of solid product (yield: 98%). Under argon protection, 16 mg of the above solid was dissolved with 51 mg of SAC-0906 in 1 mL of pyridine (Aldrich) and stirred at 80 °C for 4 hours. After the reaction was completed, it was cooled to room temperature, acidified by adding 2N hydrochloric acid solution, extracted with 20 mL of ether, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with the eluent of ethyl acetate/hexane (1:5) to afford O-isobutylhydroxylamine hydrochloride SAC-1016 (53 mg, yield: 89%).1H-NMR (300 MHz, CDCl3) δ 5.91-5.76 (m, 2H), 5.34-5.32 (m, 1H), 5.27 -5.24 (m, 1H), 5.14 (m, 1H), 4.24-4.10 (m, 3H), 4.00-3.96 (m, 2H), 3.61-3.49 (m, 1H), 2.41-0.60 (m, 44H).
References
[1] Patent: US2014/378399, 2014, A1. Location in patent: Paragraph 0102
[2] Journal of Pharmacology and Experimental Therapeutics, 1999, vol. 288, # 2, p. 490 - 501
[3] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 184 - 194
[4] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 7, p. 1844 - 1848
