反应详情

A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 1 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-ethynyl-4-fluoroaniline (J. Org. Chem., 1981, 46, 2280-2286) (1.49 g, 11.0 mmol) and dry DMA (15 mL). The residue of 3-ethynyl-4-fluoroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 45 h. It was poured into water (300 mL). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (5×50 mL); ethyl acetate/petroleum ether (1:10) (4×50 mL) and dried to give N-(3-ethynyl-4-fluorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (208) (2.39 g, 85%) as a pale brown solid, mp 223-226° C.; 1H NMR δ [(CD3)2SO] 10.10 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.24 (br s, 1H),), 8.12 (dd, J=6.4, 2.8 Hz, 1H), 7.96-7.88 (m, 1H), 7.39 (t, J=9.1 Hz, 1H), 4.54 (s, 1H). Anal. Calcd for C15H8F2N4.1.8H2O: C, 57.25; H, 3.72; N, 17.80. Found C, 57.27; H, 3.49; N, 17.90.

1. temperatureunder reflux for 1 h
2. customto give a homogeneous mixture
3. customIt was evaporated under reduced pressure at 45° C. (bath temperature)
4. customto give a light brown solid
5. washThe residue of 3-ethynyl-4-fluoroaniline was washed down with more DMA (2×2 mL)
6. additionIt was poured into water (300 mL)
7. customat room temperature
8. additionPetroleum ether (300 mL) was added
9. stirringstirred at room temperature for 30 min
10. customThe petroleum ether layer was decanted
11. filtrationThe solid was collected by filtration
12. washwashed with water (5×50 mL)
13. dry with materialethyl acetate/petroleum ether (1:10) (4×50 mL) and dried