反应详情

6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (153.3 mg, 0.3441 mmol) was suspended in ethanol (3.0 mL) and dichloromethane (3.0 mL), 3-aminopyridine (65.9 mg, 0.700 mmol) and tetraisopropoxytitanium (0.15 mL, 0.51 mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (50° C.-60° C.) and stirred under nitrogen for 6 hours. Then, the reaction was cooled to room temperature and allowed to stir overnight. After stirring overnight, sodium borohydride (26.7 mg, 0.706 mmol) was added, and stirring was continued at room temperature. After 35 minutes, the reaction was treated with 5N HCl (0.60 mL) added dropwise, as gas evolution occurs. The reaction was diluted with MeOH (about 1 mL, both before and after adding the HCl) and stirred at room temperature for 5 hours. Then, the reaction flask was fitted with a reflux condenser and put in an oil bath which was heated to 50° C. Stirring was continued at this temperature for 1 hour, and then the reaction was cooled to room temperature. The suspension was diluted with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated and treated with water and filtered. The solid was collected and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-3-ylamino)methyl)pyridin-2-amine (27.3 mg, 18%). MS (ESI pos. ion) m/z 440 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 13.63 (br s, 1H), 12.59 (s, 1H), 9.79 (s, 1H), 8.57 (s, 1H), 8.54 (d, J=2.74 Hz, 1H), 8.35 (d, J=2.35 Hz, 1H), 8.19-8.10 (m, 2H), 8.04 (d, J=1.56 Hz, 1H), 7.75-7.68 (m, 2H), 7.57 (br s, 1H), 6.85 (d, J=8.80 Hz, 1H), 4.45 (s, 2H), 3.85 (s, 3H), 2.85 (s, 3H).

1. customThe flask was fitted with a reflux condenser
2. customplaced in a preheated oil bath
3. stirringto stir overnight
4. stirringAfter stirring overnight
5. stirringstirring
6. customwas continued at room temperature
7. waitAfter 35 minutes
8. additionadded dropwise, as gas evolution
9. stirringstirred at room temperature for 5 hours
10. customThen, the reaction flask was fitted with a reflux condenser
11. customput in an oil bath
12. temperaturewhich was heated to 50° C
13. stirringStirring
14. waitwas continued at this temperature for 1 hour
15. temperaturethe reaction was cooled to room temperature
16. filtrationfiltered through a Celite® (diatomaceous earth) pad, which
17. washwas washed with DCM and MeOH
18. concentrationThe filtrate was concentrated
19. additiontreated with water
20. filtrationfiltered
21. customThe solid was collected
22. custompurified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min)