反应详情

To a cloudy suspension of 2-chloro-5-nitrobenzoic acid (1.0 g, 4.96 mmol) and DMF (0.019 mL, 0.25 mmol) in DCM (12.4 mL) at 0° C. was added a 2M solution of oxalyl chloride in DCM (2.98 mL, 5.95 mmol). The resulting suspension was stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and azeotroped with toluene to remove HCl and oxalyl chloride. The residue was dissolved in tetramethylenesulfone (12.4 mL), to which potassium carbonate (1.37 g, 9.92 mmol) and 1H-1,2,3-triazole (0.29 mL, 4.96 mmol) were added. The mixture was heated to 150° C. under nitrogen for 1 hour. The mixture was cooled and diluted with EtOAc and water. The layers were separated, and the aqueous phase extracted three times with EtOAc (50 mL). The organics were combined, washed with water and brine, and then dried over anhydrous magnesium sulfate. Filtration and concentration afforded a dark brown oil which was dissolved in a small amount of DCM and charged to a 80 g silica gel cartridge which was eluted at 65 mL/min. with a 25 min. gradient from 100% to 50% EtOAc/hexanes (monitoring at 254 nm). Concentration of the appropriate fractions afforded Intermediate 56A (0.431 g, 39% yield) as a light yellow solid. HPLC: Rt=3.246 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=225.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (1H, d, J=2.77 Hz), 8.42 (1H, s), 8.33 (1H, dd, J=8.81, 2.77 Hz), 7.95 (1H, d, J=8.81 Hz), 7.56 (1H, s).

1. concentrationThe reaction mixture was concentrated in vacuo
2. customazeotroped with toluene
3. customto remove HCl and oxalyl chloride
4. additionwere added
5. temperatureThe mixture was heated to 150° C. under nitrogen for 1 hour
6. temperatureThe mixture was cooled
7. customThe layers were separated
8. extractionthe aqueous phase extracted three times with EtOAc (50 mL)
9. washwashed with water and brine
10. dry with materialdried over anhydrous magnesium sulfate
11. filtrationFiltration and concentration
12. customafforded a dark brown oil which
13. additioncharged to a 80 g silica gel cartridge which
14. washwas eluted at 65 mL/min. with a 25 min. gradient from 100% to 50% EtOAc/hexanes (monitoring at 254 nm)