反应详情

温度

2.5 °C

A 250 mL-3N-RBF was charged with 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione and H2O (10 vol) and cooled to 0-5° C. NaNO2 (1.1 eq) and HCl (1.1 eq) were added, and the mixture was stirred for 30 minutes. The mixture was then heated to 75-80° C. for 2 hours. The mixture was cooled to room temperature, filtered and dried in vacuo (18 h, 35-40° C.). The crude product was purified by prep-HPLC (Conditions: C18 Symmetry Column, 90:10 H2O: MeCN isocratic, 60 mL/min flow rate, product retention time ˜30 min) to give an off-white solid (240 mg, 2.4%, 99.5 HPLC AP); mp 296.39° C.; HPLC: Hypersil DBS C8 5 m column, 250×4.6 mm, 35° C.; 99:1 to 85:15 Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min over 20 minutes; 7.60 min, 99.5% AP at 210/240 nm: 1H-NMR (DMSO-d6): 10.97 (1H, br s), 10.11 (1H, br s), 7.34 (1H, t), 7.17 (1H, d), 7.03 (1H, d), 5.09 (1H, dd), 4.25 (2H, dd), 2.97-2.85 (1H, m), 2.62-2.36 (2H, m), 2.03-1.96 (1H, m) ppm; 13C-NMR (DMSO-d6): 172.85, 171.04, 168.27, 152.55, 133.41, 129.44, 127.94, 117.97, 113.71, 51.59, 45.09, 31.22, 22.42 ppm; LC-MS ES+ (M+1) 261; CHN-Analysis, calcd for C13H12N2O4: C, 60.00%; H, 4.65%; N, 10.76%. Found: C, 59.54%; H, 4.88%; N, 10.48%.

1. temperatureThe mixture was then heated to 75-80° C. for 2 hours
2. temperatureThe mixture was cooled to room temperature
3. filtrationfiltered
4. customdried in vacuo (18 h, 35-40° C.)
5. customThe crude product was purified by prep-HPLC (Conditions: C18 Symmetry Column, 90:10 H2O: MeCN isocratic, 60 mL/min flow rate, product retention time ˜30 min)
6. customto give an off-white solid (240 mg, 2.4%, 99.5 HPLC AP)
7. custom7.60 min, 99.5% AP