反应详情

温度

28 °C

To N-(3-aminopropyl)morpholine (86.90 g, 602.52 mmol) which was cooled to 3° C. was in several times added 3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl methanesulfonate (amount corresponding to dried weight 15.00 g (40.17 mmol)) not to exceed to 20° C. After stirring at 28° C. for 10 hours, thereto was added 15% brine (160.00 g), and the mixture was extracted with a mixture of toluene (194.08 g) and THF (199.8 g). After removal of the organic solvent, concentrated hydrochloric acid (41.84 g) was added thereto, and the mixture was stirred at 25° C. for 3 hours. After removal by distillation of the solvent, to the residue was added methanol (118.65 g), followed by raising to 55° C. Isopropanol (353.25 g) was dropped thereto and the mixture was crystallized and further raised to 70° C. After one hour, the mixture was cooled to 20° C. The resulting crystal was filtered, washed and dried to give the subject compound (16.80 g, 77.5% by 2 steps). Purity: 99.70% (HPLC)

1. customto exceed to 20° C
2. extractionthe mixture was extracted with a mixture of toluene (194.08 g) and THF (199.8 g)
3. customAfter removal of the organic solvent, concentrated hydrochloric acid (41.84 g)
4. additionwas added
5. stirringthe mixture was stirred at 25° C. for 3 hours
6. customAfter removal
7. distillationby distillation of the solvent
8. additionto the residue was added methanol (118.65 g)
9. temperatureby raising to 55° C
10. additionIsopropanol (353.25 g) was dropped
11. customthe mixture was crystallized
12. temperaturefurther raised to 70° C
13. waitAfter one hour
14. temperaturethe mixture was cooled to 20° C
15. filtrationThe resulting crystal was filtered
16. washwashed
17. customdried
18. customto give the subject compound (16.80 g, 77.5% by 2 steps)