反应详情

温度

70 °C

A stirred mixture of N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(piperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.350 g, 0.509 mmol) in dichloromethane (10 mL) was treated with triethylamine (0.355 mL, 2.54 mmol). After 10 min, methanesulfonyl chloride (Aldrich; 0.119 mL, 1.526 mmol) was added into the mixture slowly via syringe. After the addition, the reaction mixture was placed into a pre-heated (70° C.) bath and allowed to stir under inert atmosphere for 1.5 h. The heating bath was removed and the mixture was allowed to cool to ambient temperature. The mixture was diluted with chloroform (20 mL) and water (10 mL) and the organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica-gel column (40 g) eluting with 20% methanol/dichloromethane to give the bis-PMB protected material as a tan oil. This material was diluted with trifluoroacetic acid (1.8 mL, 23.36 mmol) and allowed to stir 5 min. Then trifluoromethanesulfonic acid (0.2 mL, 2.252 mmol) was added into the mixture. The mixture was placed into a pre-heated (70° C.) bath and allowed to stir under inert atmosphere for 10 min. The heating bath was removed and the mixture was allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The mixture was diluted with dichloromethane (10 mL) and sodium carbonate (1.00 g) was added into the mixture, then allowed to stir for 5 min. Then methanol (3 mL) was added into the mixture and allowed to stir 20 min. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was recrystallized from ethyl acetate/diethyl ether to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.035 g, 0.067 mmol, 17.71% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 12.23 (s, 1H) 9.36 (s, 1H) 8.92 (s, 1H) 8.74 (s, 1H) 8.39 (s, 1H) 8.05 (s, 1H) 7.91 (s, 1H) 7.79 (m, 2H) 3.59 (m, 1H) 3.10 (s, 4H) 2.86 (s, 3H) 2.50 (d, J=8.80 Hz, 4H) 1.99 (s, 3H) 1.38 (d, J=6.06 Hz, 3H). m/z (ESI, +ve ion) 526.0 (M+H)+.

1. additionAfter the addition
2. customThe heating bath was removed
3. temperatureto cool to ambient temperature
4. additionThe mixture was diluted with chloroform (20 mL) and water (10 mL)
5. extractionthe organic layer was extracted with chloroform (3×10 mL)
6. dry with materialThe combined organic extracts were dried (magnesium sulfate)
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. custompurified by chromatography through a silica-gel column (40 g)
10. washeluting with 20% methanol/dichloromethane
11. customto give the bis-PMB
12. stirringto stir 5 min
13. temperaturea pre-heated (70° C.) bath
14. stirringto stir under inert atmosphere for 10 min
15. customThe heating bath was removed
16. temperatureto cool to ambient temperature
17. concentrationThe mixture was concentrated in vacuo
18. additionThe mixture was diluted with dichloromethane (10 mL) and sodium carbonate (1.00 g)
19. additionwas added into the mixture
20. stirringto stir for 5 min
21. additionThen methanol (3 mL) was added into the mixture
22. stirringto stir 20 min
23. filtrationThe mixture was filtered
24. concentrationthe filtrate was concentrated in vacuo
25. customThe crude product was recrystallized from ethyl acetate/diethyl ether