反应详情

温度

40 °C

To a stirred mixture of CDI (0.53 g, 3.25 mmol) and dry THF (2 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (0.64 g, 3.25 mmol) in THF (1 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 15 min (whence evolution of gases ceased). A solution of compound 219 (1.03 g, 2.50 mmol) in a mixed solvents of dry THF (2.5 mL) and DMA (2.5 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=20:1) and found only ca. 60% reaction occurred after 50 min. Thus, another batch of reagent was prepared from CDI [0.53 g, 3.25 mmol; dry THF (2 mL)] and 2-(diethoxyphosphoryl)acetic acid [0.64 g, 3.25 mmol); THF (1 mL)] and added to the reaction. It was stirred further for 3 h at 40° C. The reaction mixture was poured into water (300 mL) and stirred with petroleum ether (400 mL) at room temperature for 12 h. Petroleum ether layer was decanted. More petroleum ether (200 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (5×20 mL) and dried to give diethyl 2-(4-(3-chloro-4-(3-chlorobenzyloxy)phenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (228) (1.37 g, 93%); mp 106-109° C.; 1H NMR δ (CDCl3) 9.41 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1 H), 7.91 (d, J=2.6 Hz, 1H), 7.66 (s, 1H), 7.54 (dd, J=8.8, 2.6 Hz, 1H), 7.48 (s, 1H), 7.40-7.29 (m, 3H), 6.99 (d, J=8.9 Hz, 1H), 5.15 (s, 2H), 4.30-4.18 (m, 4H), 3.15 (d, J=21.1 Hz, 2H), 1.39 (t, J=7.0 Hz, 6H). δ [(CD3)2SO]: 10.82 (s, 1H), 10.25 (s, 1H), 8.99 (poorly resolved d, J=0.6 Hz, 1H), 8.41 (s, 1H), 8.58 (s, 1 H), 7.95 (d, J=2.6 Hz, 1H), 7.71 (dd, J=9.0, 2.6 Hz, 1H), 7.56 (br s, 1H), 7.50-7.38 (m, 3H), 7.27 (d, J=9.0 Hz, 1H), 5.26 (s, 2H), 4.15-4.04 (m, 4H), 3.34 (d, partially obscured by water peak, 2H), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C26H26Cl2N5O3P.0.5H2O: C, 52.10; H, 4.54; N, 11.68%. Found C, 52.09; H, 4.60; N, 11.70%.

1. additionAfter addition the reaction mixture
2. stirringstirred further at 40° C
3. customca. 60% reaction
4. waitoccurred after 50 min
5. stirringIt was stirred further for 3 h at 40° C
6. customPetroleum ether layer was decanted
7. additionMore petroleum ether (200 mL) was added
8. stirringstirred for 15 min
9. filtrationThe solid was collected by suction filtration
10. washwashed with water (5×20 mL)
11. customdried