反应详情

6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (187.1 mg, 0.4200 mmol) was suspended in EtOH (3.8 mL) and tetraisopropoxytitanium (Fluka, Buchs, Switzerland, 0.25 mL, 0.84 mmol) and 4-methoxyaniline (Aldrich, St. Louis, Mo., 81.9 mg, 0.665 mmol) were added. DCM (2 mL) was added about 15 minutes later, and the reaction was stirred under nitrogen at room temperature overnight. Then, sodium borohydride (36 mg, 0.95 mmol) was added along with DCM (3 mL), and stirring was continued at room temperature, resulting in precipitation. After stirring for 1 hour, the suspension was treated with MeOH (1.5 mL) and 5 N HCl (0.60 mL). Stirring was continued at room temperature overnight. Then, the reaction was treated with water (20 mL) and filtered, and the solid was washed with water. The solid and unfiltered material were combined, concentrated, and treated with MeOH, and filtered. The filtration was sluggish, so instead the suspension was concentrated, treated with TFA and DMSO, and filtered with DCM and MeOH. This filtration was also sluggish, so the suspension was filtered instead through a Celite® (diatomaceous earth) pad. The filtrate was concentrated, but could not be filtered for HPLC purification despite treatment with DMSO, TFA, MeOH, and DCM. So, this solution was concentrated, and the fine suspension was filtered through a Celite® (diatomaceous earth) pad. This filtrate was purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give 5-((4-methoxyphenylamino)methyl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (149.4 mg, 76% yield). MS (ESI pos. ion) m/z 469 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.60 (s, 1H), 9.72 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=2.54 Hz, 1H), 8.27 (s, 1H), 8.14 (dd, J=9.10 Hz, 2.45 Hz, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 6.97 (s, 2H), 6.90-6.80 (m 3H), 4.38 (s, 2H), 3.85 (s, 3H), 3.67 (s, 3H), 2.85 (s, 3H).

1. stirringstirring
2. customwas continued at room temperature
3. customresulting in precipitation
4. stirringAfter stirring for 1 hour
5. stirringStirring
6. waitwas continued at room temperature overnight
7. filtrationfiltered
8. washthe solid was washed with water
9. concentrationconcentrated
10. additiontreated with MeOH
11. filtrationfiltered
12. filtrationThe filtration
13. concentrationso instead the suspension was concentrated
14. additiontreated with TFA and DMSO
15. filtrationfiltered with DCM and MeOH
16. filtrationThis filtration
17. filtrationso the suspension was filtered instead through a Celite® (diatomaceous earth) pad
18. concentrationThe filtrate was concentrated
19. filtrationcould not be filtered for HPLC purification despite treatment with DMSO, TFA, MeOH, and DCM
20. concentrationSo, this solution was concentrated
21. filtrationthe fine suspension was filtered through a Celite® (diatomaceous earth) pad
22. customThis filtrate was purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min)