反应详情

温度

0 °C

Separately, 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethanol (231 mg, 0.501 mmol) was dissolved in DCM (10 mL) and triethylamine (Aldrich 99.5%, 0.28 ml, 2.0 mmol) was added. The reaction was cooled in an ice water bath, and methanesulfonyl chloride (0.15 mL, 1.9 mmol) was added. The reaction was stirred at 0° C. for 15 min, and then 1-methanesulfonylpiperazine (474.4 mg, 2.89 mmol) was added, causing precipitation. The reaction was warmed to room temperature and stirring was continued. After 2 h, the reaction was diluted with MeOH (10 mL) and 5 N HCl (2.0 mL) was added. Stirring was continued at room temperature. After another hour, this reaction was combined with the other reaction, treated with 5 N NaOH and 5 N HCl to adjust the pH to around 6, and allowed to stand at room temperature over the weekend. The resultant suspension was filtered, and the solid was washed with DCM and MeOH. The filtrate was concentrated and treated with water and filtered. The solid was washed with water. The filtrate was discarded. The solid was collected and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min.) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-amine (81.0 mg, 24% yield) as a TFA salt. 1H NMR (d6-DMSO, 400 MHz) δ 12.61 (br s, 1H), 9.78 (s, 1H), 8.67 (s, 1H), 8.54 (d, J=2.54 Hz, 1H), 8.40 (d, J=2.35 Hz, 1H), 8.16 (dd, J=9.0 Hz, 2.74 Hz, 1H), 6.87 (d, J=8.80 Hz, 1H), 4.69 (br, s, 1H), 3.85 (s, 3H), 3.45-3.00 (m, 6H), 2.98 (s, 3H), 2.86 (s, 3H), 1.76 (d, J=7.04 Hz, 3H). m/z (ESI, pos. ion) 524 (M+H)+.

1. temperatureThe reaction was cooled in an ice water bath
2. customprecipitation
3. temperatureThe reaction was warmed to room temperature
4. stirringstirring
5. waitAfter 2 h
6. additionthe reaction was diluted with MeOH (10 mL) and 5 N HCl (2.0 mL)
7. additionwas added
8. stirringStirring
9. customwas continued at room temperature
10. waitAfter another hour
11. customthis reaction was combined with the other reaction
12. customto stand at room temperature over the weekend
13. filtrationThe resultant suspension was filtered
14. washthe solid was washed with DCM and MeOH
15. concentrationThe filtrate was concentrated
16. additiontreated with water
17. filtrationfiltered
18. washThe solid was washed with water
19. customThe solid was collected
20. custompurified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min