反应详情

温度

75 °C

A suspension of 2-chloro-5-(((3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (0.236 g, 0.543 mmol), iron (325 mesh) (0.152 g, 2.71 mmol), and ammonium chloride (0.015 g, 0.271 mmol) in EtOH (3 mL) and water (0.5 mL) was stirred at 75° C. for 45 min. The reaction was cooled to rt and filtered through a pad of celite. The celite was washed with EtOAc, and the combined filtrates were partitioned between EtOAc and saturated sodium bicarbonate solution and 1 N NaOH (1:1). The organic layer was dried over Na2SO4, filtered, and concentrated to a purple foam. This residue was dissolved in formic acid (0.060 mL, 1.56 mmol) and trimethyl orthoformate (1.72 mL, 15.6 mmol). The resulting solution was stirred at rt for 18 h. The reaction mixture was concentrated and redissolved in EtOAc. The organic solution was washed with saturated sodium bicarbonate solution and concentrated. The crude product was purified using reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 16 minute run; 50 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 30-70% solvent A) to afford the title compound (0.125 g, 57% yield) as the TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 4.07 (ddd, J=7.53, 14.56, 24.85 Hz, 2H), 3.36 (dd, J=8.53, 24.09 Hz, 2H), 3.00 (dd, J=14.31, 32.37 Hz, 2H), 2.37-2.52 (m, 1H), 2.03 (d, J=16.81 Hz, 1H), 1.94 (dd, J=2.01, 12.80 Hz, 1H), 1.64-1.82 (m, 3H), 1.31-1.44 (m, 1H), 1.22 (t, J=12.80 Hz, 1H), 0.98-1.11 (m, 1H), 0.95 (s, 9H). MS (m/z) 415.2 (M+H+).

1. temperatureThe reaction was cooled to rt
2. filtrationfiltered through a pad of celite
3. washThe celite was washed with EtOAc
4. customthe combined filtrates were partitioned between EtOAc and saturated sodium bicarbonate solution and 1 N NaOH (1:1)
5. dry with materialThe organic layer was dried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated to a purple foam
8. stirringThe resulting solution was stirred at rt for 18 h
9. concentrationThe reaction mixture was concentrated
10. dissolutionredissolved in EtOAc
11. washThe organic solution was washed with saturated sodium bicarbonate solution
12. concentrationconcentrated
13. customThe crude product was purified
14. customreverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 16 minute run; 50 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 30-70% solvent A)