反应详情

温度

100 °C

A mixture of 5-bromo-3-chloro-2-methylquinoxaline (126e, 7.25 g, 28.2 mmol) and (rac)-1,3-cyclohexanediamine (TCI America, Inc., Portland, Oreg.; 23.69 m, 197 mmol) in DMSO (28.2 mL) was heated to 100° C. for 16 h. The reaction was cooled to RT and diluted with water. It was extracted with EtOAc (3×), dried over MgSO4, filtered, and concentrated to give (N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483a, 14.25 g, 151% yield) a dark orange-brown oil. MS (ESI, pos. ion) m/z: 335.0/337.0 (M+1). Separation of (1S,3R)—N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine. The racemic mixture was separated using chiral SFC via two purifications. 1st Purification: Preparative SFC: AY-H (5 μm, 21 mm×25 cm) with 20% organic modifier: 80% carbon dioxide. Organic modifier: methanol with 0.2% diethylamine. F=70 ml/min, T=40° C., BPR=100 bar, P=179 bar, 256 nm. (N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483a, 14.25 g) dissolved in methanol (250 mL, 60 mg/mL). 0.5 mL injection. Two peaks were collected. 2nd Purification: Preparative SFC: Repurification of peak 2. OJ-H (5 μm, 21 mm×25 cm, S/N=0131) with 20% organic modifier modifier: 80% carbon dioxide. Organic modifier: methanol with 0.2% diethylamine. F=70 mL/min, T=40° C., BPR=100 bar, P=172 bar, 256 nm. Peak 2 from the 1st purification was dissolved in methanol (60 mL). 0.6 mL injection. A single peak was collected to give (1S,3R)—N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483b, 2.81 g, 30% recovery) as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (1H, d, J=7.63 Hz) 7.70 (1H, d, J=8.02 Hz) 7.15-7.26 (2H, m) 4.17 (1H, br. s.) 2.76 (1H, t, J=10.17 Hz) 2.52 (3H, br. s.) 2.08 (1H, d, J=12.13 Hz) 1.95 (1H, br. s.) 1.76 (2H, d, J=9.19 Hz) 1.26-1.41 (3H, m) 1.02-1.17 (1H, m). MS (ESI, pos. ion) m/z: 335.0/337.0 (M+1).

1. temperatureThe reaction was cooled to RT
2. extractionIt was extracted with EtOAc (3×)
3. dry with materialdried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated