反应详情

To a 25 mL vial with magnetic stirring were added 4-amino-5-fluoro-1-((4-methoxyphenyl)sulfonyl)pyrimidin-2(1H)-one (150 mg, 0.501 mmol), thiophen-2-ylmethanol (172 mg, 1.504 mmol), triphenylphosphine (Ph3P; 394 mg, 1.504 mmol) and dry tetrahydrofuran (THF; 4.204 mL). The reaction mixture was placed under nitrogen (N2) atmosphere and cooled to ice-bath temperature. After cooling 10 minutes (min), diethylazodicarboxylate (DEAD; 0.238 mL, 1.504 mmol) was added dropwise and the mixture was allowed to warm to room temperature overnight. The reaction mixture was evaporated to dryness. The crude residue was purified on SiO2 (EtOAc/hexanes gradient) to provide the title compound as a yellow-white wax (146 mg, 73.8%): 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=9.1 Hz, 2H), 7.84 (d, J=1.8 Hz, 1H), 7.67 (d, J=5.5 Hz, 1H), 7.17 (dd, J=5.2, 1.2 Hz, 1H), 7.13 (d, J=3.5 Hz, 1H), 7.02 (d, J=9.1 Hz, 2H), 6.88 (dd, J=5.1, 3.5 Hz, 1H), 5.28 (s, 2H), 3.91 (s, 3H);. UV (CH2Cl2) λmax: 259 nm; ESIMS m/z 396.5 ([M+H]+). Step 2: 5-Fluoro-4-imino-3-(thiophen-2-ylmethyl)-3,4-dihydropyrimidin-2(1H)-one (2). To a magnetically stirred mixture of 5-fluoro-4-imino-1-((4-methoxyphenyl)sulfonyl)-3-(thiophen-2-ylmethyl)-3,4-dihydropyrimidin-2(1H)-one (130 mg, 0.329 mmol) in dry TFA (2.529 mL) was added dimethyl sulfide (0.122 mL, 1.64 mmol) in a dry 25 mL vial under Argon atmosphere. The reaction mixture was stirred at 23° C. for 16 h. The reaction mixture was evaporated to dryness and the crude residue was diluted with ice-water and aqueous saturated sodium bicarbonate solution and extracted with CH2Cl2 (2×). The layers were separated, the combined organic extracts were evaporated, and the crude residue was purified on SiO2 (EtOAc/CH2Cl2 gradient) to afford the title compound as an off-white wax (15 mg, 19.2%): 1H NMR (400 MHz, CDCl3+D2O) δ 7.22 (br d, J=3.4 Hz, 1H), 7.21 (dd, J=5.2, 1.1 Hz, 1H), 6.94 (dd, J=5.1, 3.5 Hz, 1H), 6.72 (d, J=4.3 Hz, 1H), 5.38 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 152.48 (d, J=30.5 Hz), 151.06 (s), 138.17 (s), 137.82 (s), 128.48 (s), 126.30 (s), 125.76 (s), 115.39 (d, J=35.1 Hz), 39.30 (s); ESIMS m/z 226.3 ([M+H]+), 224.4 ([M−H]−).

1. temperaturecooled to ice-bath temperature
2. additionwas added dropwise
3. customThe reaction mixture was evaporated to dryness
4. customThe crude residue was purified on SiO2 (EtOAc/hexanes gradient)