Synthesis
1. 500 mg of hydroxyphthalimide (Aldrich) was dissolved in 5 mL of dimethylformamide (DMF) under argon protection.
2. 0.38 mL of 1-iodobutane (Aldrich) and 0.5 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, Aldrich) were added sequentially and slowly.
3. The reaction mixture was stirred at 60 °C for 2 h and subsequently cooled to room temperature.
4. The reaction was terminated by addition of 2 N hydrochloric acid solution and the reaction solution was diluted with 20 mL of ethyl acetate.
5. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
6. The residue was purified by silica gel column chromatography using ethyl acetate/hexane (1:5) as eluent to give 635 mg of the target compound (95% yield).
7. The above compound was dissolved in 5 mL of dichloromethane and 0.12 mL of methylhydrazine (TCI) was added slowly at 0 °C.
8. The reaction solution was stirred at room temperature for 2 hours and then cooled to 0°C again.
9. The resulting solid was collected by filtration and 1 mL of 4 M dioxane hydrochloride solution (Aldrich) was added to the filtrate, which was filtered and dried to give 257 mg solid (100% yield).
10. 13 mg of the above solid was dissolved with 44 mg of SAC-0906 in 1 mL of pyridine (Aldrich) under argon protection and stirred at 80 °C for 4 hours.
11. The reaction solution was cooled to room temperature, acidified with 2 N hydrochloric acid solution and extracted with 20 mL of ether.
12. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
13. The residue was purified by silica gel column chromatography using ethyl acetate/hexane (1:5) as eluent to afford O-butylhydroxylamine hydrochloride SAC-1015 (44 mg, 88% yield).
14. The product was characterized by 1H-NMR (300 MHz, CDCl3): δ 5.91-5.76 (m, 2H), 5.34-5.33 (m, 1H), 5.28-5.25 (m, 1H), 5.15 (m, 1H), 4.25-4.10 (m, 3H), 4.02-3.97 (m, 2H), 3.59-3.48 (m, 1H), 3.59-3.48 (m, 2H). (m, 1H), 2.42-0.60 (m, 42H).
References
[1] Patent: US2014/378399, 2014, A1. Location in patent: Paragraph 0100
[2] Farmaco, Edizione Scientifica, 1987, vol. 42, # 10, p. 697 - 708
[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
