反应详情

Isopropyl chloroformate (1 M in toluene, 1.155 mL, 1.155 mmol) and then N-methyl morpholine (0.127 mL, 1.155 mmol) were added to a stirred solution of 2-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanoic acid (0.25 g, 1.050 mmol) in dimethylformamide (1.34 mL) under nitrogen at −10° C. to −15° C. The reaction was stirred for one hour at this temperature then morpholine (0.183 g, 2.100 mmol) and triethylamine (0.146 mL, 1.050 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was stirred at −10° C. to −15° C. for one hour then allowed to warm to room temperature. After 16 hours, ether (5 mL) was added and the resulting precipitate was washed with ether (2×5 mL), acetonitrile (2×5 mL), dichloromethane (2×5 mL) and ether (2×5 mL) then purified by flash column chromatography (SiO2, 9:1 acetonitrile/dichloromethane) and triturated with ether to furnish the desired product as a white solid. Yield: 105 mg, 0.34 mmol, 33%. LCMS (ES+) m/z 308 (M+H)+ at 0.97 minutes. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (1H, s), 7.83 (1H, br s), 7.68 (1H, bs), 5.35 (2H, s), 3.66 (2H, m), 3.51-3.60 (4H, overlapping multiplets), 3.45 (2H, m).

1. stirringThe reaction mixture was stirred at −10° C. to −15° C. for one hour
2. waitAfter 16 hours
3. washthe resulting precipitate was washed with ether (2×5 mL), acetonitrile (2×5 mL), dichloromethane (2×5 mL) and ether (2×5 mL)
4. customthen purified by flash column chromatography (SiO2, 9:1 acetonitrile/dichloromethane)
5. customtriturated with ether