反应详情

温度

40 °C

To a stirred mixture of CDI (1.41 g, 8.73 mmol) and dry THF (6 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (1.56 g, 7.94 mmol) in THF (4 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 220 (1.53 g, 3.97 mmol) in a mixed solvents of dry THF (4 mL) and DMA (5 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=15:1). After stirred overnight (16 h), it was found only ca. 70% reaction occurred. Thus, another batch of reagent was prepared from CDI [0.42 g, 2.62 mmol; DCM (3 ml)] and 2-(diethoxyphosphoryl)acetic acid [0.47 g, 2.38 mmol); DCM (2 mL)] and added to the reaction. It was stirred further for 4 h at 40° C. The reaction mixture was poured into water (200 mL) and stirred with petroleum ether (400 mL) at room temperature for 20 min. Petroleum ether layer was decanted. It was repeated once more with petroleum ether (200 mL). The sticky solid was collected by suction filtration; washed with water (5×30 mL). It was dissolved in acetone (50 mL) and stirred with water (100 mL) and petroleum ether (200 mL) at room temperature for 68 h. The solid was collected, washed with acetone/water=1:10 (5×30 mL) and dried to give diethyl 2-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (229) (1.95 g, 87%); mp 111-114° C.; 1H NMR δ [(CD)2SO]: 10.81 (s, 1H), 10.36 (s, 1H), 8.98 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1 H), 8.16 (d, J=0.7 Hz, 1H), 8.13 (d, J=1.3 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.68 (dd, J=9.0, 1.8 Hz, 1H), 7.42-7.32 (m, 1H), 7.15-7.00 (m, 3H), 5.70 (s, 2 H), 4.17-4.03 (m, 4H), 3.32 (d, partially obscured by water peak, 2H), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C27H27FN7O4P.1.6H2O: C, 54.75; H, 5.14; N, 16.55%. Found C, 54.60; H, 5.21; N, 16.60%.

1. additionAfter addition the reaction mixture
2. stirringstirred further at 40° C
3. stirringAfter stirred overnight (16 h), it
4. customca. 70% reaction
5. stirringIt was stirred further for 4 h at 40° C
6. customPetroleum ether layer was decanted
7. filtrationThe sticky solid was collected by suction filtration
8. washwashed with water (5×30 mL)
9. dissolutionIt was dissolved in acetone (50 mL)
10. stirringstirred with water (100 mL) and petroleum ether (200 mL) at room temperature for 68 h
11. customThe solid was collected
12. washwashed with acetone/water=1:10 (5×30 mL)
13. customdried